ORCID Profile
0000-0002-5715-1534
Current Organisation
Monash University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Wiley
Date: 12-01-2007
Publisher: Springer Science and Business Media LLC
Date: 27-03-2009
DOI: 10.1007/S10928-009-9115-Y
Abstract: This study explored how study design influences the probability of selecting a 'true' covariate from two competing covariate models. The probability of selecting the 'True Model' (lean body weight on clearance) over the 'False Model' (total body weight (WT) on clearance) was compared for designs where WT was either lognormally distributed (i.e. non-stratified), or stratified into 3 equal strata. The probability of selecting the 'True Model' increased as the WT inclusion criterion widened, and was always greater under the stratified design. Incorporating stratification into study designs, in combination with a wide covariate range, can aid identification of true parameter-covariate relationships. This has particular importance if the model is to be extrapolated beyond the studied population (e.g. dosing in obesity).
Publisher: American Society for Microbiology
Date: 09-2010
DOI: 10.1128/AAC.00222-10
Abstract: The objective of the present prospective pharmacokinetic study was to describe the variability of plasma gentamicin concentrations in critically ill patients with acute kidney injury (AKI) necessitating extended daily diafiltration (EDD-f) using a population pharmacokinetic model and to subsequently perform Monte Carlo dosing simulations to determine which dose regimen achieves the pharmacodynamic targets the most consistently. We collected data from 28 gentamicin doses in 14 critically ill adult patients with AKI requiring EDD-f and therapeutic gentamicin. Serial plasma s les were collected. A population pharmacokinetic model was used to describe the pharmacokinetics of gentamicin and perform Monte Carlo simulations with doses of between 3 mg/kg of body weight and 7 mg/kg and at various time points before commencement of EDD-f to evaluate the optimal dosing regimen for achieving pharmacodynamic targets. A two-compartment pharmacokinetic model adequately described the gentamicin clearance while patients were on and off EDD-f. The plasma half-life of gentamicin during EDD-f was 13.8 h, whereas it was 153.4 h without EDD-f. Monte Carlo simulations suggest that dosing with 6 mg/kg every 48 h either 30 min or 1 h before the commencement of EDD-f results in 100% attainment of the target maximum concentration drug in plasma ( mg/liter) and sufficient attainment of the target area under the concentration-time curve from 0 to 24 h (AUC 0-24 70 to 120 mg·h/liter). None of the simulated dosing regimens satisfactorily achieved the targets of the minimum concentrations of drug in plasma ( .0 mg/liter) at 24 h. In conclusion, dosing of gentamicin 30 min to 1 h before the commencement of an EDD-f treatment enables attainment of target peak concentrations for maximal therapeutic effect while enhancing drug clearance to minimize toxicity. Redosing in many patients should occur after 48 h, and we recommend the use of therapeutic drug monitoring to guide dosing to optimize achievement of the AUC 0-24 targets.
Publisher: Oxford University Press (OUP)
Date: 25-02-2004
DOI: 10.1093/JAC/DKH146
Publisher: Cambridge University Press (CUP)
Date: 15-02-2018
DOI: 10.1017/S0950268818000158
Abstract: Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic harmacodynamics (PK/PD) – dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients’ quality of life. Integrating PK/PD–EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1053/J.AJKD.2014.06.020
Abstract: Erythropoiesis-stimulating agent (ESA)-hyporesponsive anemia is common in chronic kidney disease (CKD). Pentoxifylline shows promise as a treatment for ESA-hyporesponsive anemia, but has not been rigorously evaluated. Multicenter, double-blind, randomized, controlled trial. 53 adult patients with CKD stage 4 or 5 (including dialysis) and ESA-hyporesponsive anemia (hemoglobin≤120g/L and ESA resistance index [calculated as weight-adjusted weekly ESA dose in IU/kg/wk ided by hemoglobin concentration in g/L]≥1.0IU/kg/wk/g/L for erythropoietin-treated patients and ≥0.005μg/kg/wk/g/L for darbepoetin-treated patients). Pentoxifylline (400mg/d n=26) or matching placebo (control n=27) for 4 months. ESA resistance index at 4 months secondary outcomes: hemoglobin concentration, ESA dose, blood transfusion requirement, serum ferritin level and transferrin saturation, C-reactive protein level, adverse events, quality of life, and health economics. There was no statistically significant difference in ESA resistance index between the pentoxifylline and control groups (adjusted mean difference, -0.39 [95%CI, -0.89 to 0.10] IU/kg/wk/g/L P=0.1). Pentoxifylline significantly increased hemoglobin concentration relative to the control group (adjusted mean difference, 7.6 [95%CI, 1.7-13.5] g/L P=0.01). There was no difference in ESA dose between groups (-20.8 [95%CI, -67.2 to 25.7] IU/kg/wk P=0.4). No differences in blood transfusion requirements, adverse events, or quality of life were observed between groups. Pentoxifylline cost A$88.05 (US $82.94) per person over the trial and produced mean savings in ESA cost of A$1,332 (US $1,255). The overall economic impact over the trial period was a saving of A$1,244 (US $1,172) per person for the pentoxifylline group compared with controls. S le size smaller than planned due to slow recruitment. Pentoxifylline did not significantly modify ESA hyporesponsiveness, but increased hemoglobin concentration. Further studies are warranted to determine whether pentoxifylline therapy represents a safe strategy for increasing hemoglobin levels in patients with CKD with ESA-hyporesponsive anemia.
Publisher: Elsevier BV
Date: 02-2017
Publisher: Elsevier
Date: 2010
Publisher: Wiley
Date: 21-01-2010
Publisher: Springer Science and Business Media LLC
Date: 12-06-2023
DOI: 10.1186/S40545-023-00571-Y
Abstract: A series of Community Pharmacy Agreements (Agreements) between the Federal government and a pharmacy-owners’ body, the Pharmacy Guild of Australia (PGA) have been influential policy in Australian community pharmacy (CP) since 1990. While ostensibly to support the public’s access and use of medicines, the core elements of the Agreements have been remuneration for dispensing and rules that limit the establishment of new pharmacies. Criticism has focused on the self-interest of pharmacy owners, the exclusion of other pharmacy stakeholders from the Agreement negotiations, the lack of transparency, and the impact on competition. The objective of this paper is to determine the true nature of the policy by examining the evolution of the CPA from a policy theory perspective. A qualitative evaluation of all seven Agreement documents and their impact was undertaken using policy theories including a linear policy development model, Multiple Streams Framework, Incremental Theory, the Advocacy Coalition Framework, the Theory of Economic Regulation, the Punctuated Equilibrium Framework, and Elite Theory. The Agreements were evaluated using four lenses: their objectives, evidentiary base, stakeholders and beneficiaries. The PGA has acted as an elite organisation with long-standing influence on the policy’s development and implementation. Notable has been the failure of other pharmacy stakeholders to establish broad-based advocacy coalitions in order to influence the Agreements. The incremental changes negotiated every 5 years to the core elements of the Agreements have supported the publics’ access to medication, provided stability for the government, and security for existing pharmacy owners. Their impact on the evolution of pharmacists’ scope of practice and through that, on the public’s safe and appropriate use of medication, has been less clear. The Agreements can be characterised predominantly as industry policy benefiting pharmacy owners, rather than health policy. An emerging issue is whether incremental change will continue to be an adequate policy response to the social, political, and technological changes that are affecting health care, or whether policy disruption is likely to arise.
Publisher: Springer Singapore
Date: 19-06-2017
Publisher: Wiley
Date: 12-03-2021
DOI: 10.1002/CPT.2191
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.IJANTIMICAG.2017.02.021
Abstract: Clearance of small molecules such as amoxicillin and clavulanic acid is expected to increase during high-flux haemodialysis, which may result in lower concentrations and thus reduced efficacy. To date, clearance of amoxicillin/clavulanic acid (AMC) during high-flux haemodialysis remains largely unexplored. Using published pharmacokinetic parameters, a two-compartment model with first-order input was simulated to investigate the impact of high-flux haemodialysis on the probability of target attainment (PTA) of orally administered AMC combination therapy. The following pharmacokinetic harmacodynamic targets were used to calculate the PTA. For amoxicillin, the time that the free concentration remains above the minimum inhibitory concentration (MIC) of ≥50% of the dosing period (≥50%ƒT
Publisher: Springer Science and Business Media LLC
Date: 24-04-2015
Publisher: Springer Science and Business Media LLC
Date: 12-05-2017
Publisher: Springer Science and Business Media LLC
Date: 20-02-2011
Publisher: American Society for Microbiology
Date: 09-2007
DOI: 10.1128/AAC.01410-06
Abstract: Flucloxacillin is often used for the treatment of serious infections due to sensitive staphylococci. The pharmacokinetic (PK)-pharmacodynamic (PD) breakpoint of flucloxacillin has not been determined by the use of population PK. Targets based on the duration of non-protein-bound concentrations above the MIC ( fT MIC ) best correlate with clinical cure rates for beta-lactams. We compared the breakpoints for flucloxacillin between several dosage regimens. In a randomized, two-way crossover study, 10 healthy volunteers received 500 mg and 1,000 mg flucloxacillin as 5-min intravenous infusions. Drug concentrations were determined by high-pressure liquid chromatography. We used the programs WinNonlin for noncompartmental analysis and statistics and NONMEM for population PK and Monte Carlo simulation. We compared the probability of target attainment (PTA) for intermittent- and continuous-dosage regimens based on the targets of fT MIC s of ≥50% and ≥30% of the dosing interval. The clearance and the volume of distribution were very similar after the administration of 500 mg and 1,000 mg flucloxacillin. We estimated renal and nonrenal clearances of 5.37 liters/h (coefficient of variation, 19%) and 2.73 liters/h (33%). For near maximal killing (target, fT MIC of ≥50%) flucloxacillin showed a robust (≥90%) PTA up to MICs of 0.75 to 1 mg/liter (PTA of 86% at 1 mg/liter) for a continuous or a prolonged infusion of 6 g/day. Short-term infusions of 6 g/day had a lower breakpoint of 0.25 to 0.375 mg/liter. The flucloxacillin PK was linear for doses of 500 mg and 1,000 mg. Prolonged and continuous infusion at a 66% lower daily dose achieved the same PK-PD breakpoints as short-term infusions. Prolonged infusion and continuous infusion are appealing options for the treatment of serious infections caused by sensitive staphylococci.
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.IJANTIMICAG.2009.10.008
Abstract: The objectives of this study were (i) to compare the plasma concentration-time profiles for first-dose and steady-state piperacillin administered by intermittent or continuous dosing to critically ill patients with sepsis and (ii) to use population pharmacokinetics to perform Monte Carlo dosing simulations in order to assess the probability of target attainment (PTA) by minimum inhibitory concentration (MIC) for different piperacillin dosing regimens against bacterial pathogens commonly encountered in critical care units. Plasma s les were collected on Days 1 and 2 of therapy in 16 critically ill patients, with 8 patients receiving intermittent bolus dosing and 8 patients receiving continuous infusion of piperacillin (administered with tazobactam). A population pharmacokinetic model was developed using NONMEM, which found that a two-compartment population pharmacokinetic model best described the data. Total body weight was found to be correlated with drug clearance and was included in the final model. In addition, 2000 critically ill patients were simulated for pharmacodynamic evaluation of PTA by MIC [free (unbound) concentration maintained above the MIC for 50% of the dosing interval (50% f(T>MIC))] and it was found that continuous infusion maintained superior free piperacillin concentrations compared with bolus administration across the dosing interval. Dosing simulations showed that administration of 16g/day by continuous infusion vs. bolus dosing (4g every 6h) provided superior achievement of the pharmacodynamic endpoint (PTA by MIC) at 93% and 53%, respectively. These data suggest that administration of piperacillin by continuous infusion, with a loading dose, both for first dose and for subsequent dosing achieves superior pharmacodynamic targets compared with conventional bolus dosing.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.IJANTIMICAG.2014.07.019
Abstract: This study aimed to investigate the probability of target attainment (PTA) of various anidulafungin dosing regimens against Candida spp. in patients with acute leukaemia. A Monte Carlo simulation was performed using a previously published population pharmacokinetic model. The following dosing scenarios were evaluated: 200 mg loading dose (LD) on Day 1 then 100 mg daily (manufacturer's recommended dosing regimen) 200 mg LD on Day 1 then 100 mg every 48 h (q48 h) and 200 mg q48 h, 200 mg every 72 h (q72 h) and 300 mg q72 h. For each dosing regimen, free drug concentrations were calculated to evaluate the effect of 99% protein binding. The PTA at various pharmacodynamic (PD) targets was determined as the percentage of subjects who achieved a free drug area under the plasma concentration-time curve over the minimum inhibitory concentration ratio (ƒAUC/MIC) or a free drug maximum plasma concentration over the minimum inhibitory concentration ratio (ƒC(max)/MIC) above the PD targets. PTA expectation values were then calculated for each dosing regimen. The currently recommended dosing regimen of anidulafungin was not optimal for invasive candidiasis in patients with acute leukaemia. Alternate dosing strategies with higher doses and extended dosing intervals (intermittent dosing) achieved better target attainment. This is the first study to optimise therapy with anidulafungin using Monte Carlo simulation. These results provide a rationale in support of future clinical investigation of intermittent dosing of anidulafungin.
Publisher: Wiley
Date: 16-09-2019
DOI: 10.1002/PSP4.12460
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2011
Publisher: Elsevier
Date: 2018
Publisher: Wiley
Date: 2016
DOI: 10.1111/JGS.13877
Abstract: To investigate the effects of number of medications and Drug Burden Index (DBI) on transitions between frailty stages and death in community-dwelling older men. Cohort study. Sydney, Australia. Community-dwelling men aged 70 and older (N=1,705). Self-reported questionnaires and clinic visits were conducted at baseline and 2 and 5 years. Frailty was assessed at all three waves according to the modified Fried frailty phenotype. The total number of regular prescription medications and DBI (a measure of exposure to sedative and anticholinergic medications) were calculated over the three waves. Data on mortality over 9 years were obtained. Multistate modeling was used to characterize the transitions across three frailty states (robust, prefrail, frail) and death. Each additional medication was associated with a 22% greater risk of transitioning from the robust state to death (adjusted 95% confidence interval (CI)=1.06-1.41). Every unit increase in DBI was associated with a 73% greater risk of transitioning from the robust state to the prefrail state (adjusted 95% CI=1.30-2.31) and a 2.75 times greater risk of transitioning from the robust state to death (adjusted 95% CI=1.60-4.75). There was no evidence of an adjusted association between total number of medications or DBI and the other transitions. Although the possibility of confounding by indication cannot be excluded, additional medications were associated with greater risk of mortality in robust community-dwelling older men. Greater DBI was also associated with greater risk of death and transitioning from the robust state to the prefrail state.
Publisher: SAGE Publications
Date: 2019
Abstract: Adverse drug reactions (ADRs) have traditionally been managed by trial and error, adjusting drug and dose selection reactively following patient harm. With an improved understanding of ADRs, and the patient characteristics that increase susceptibility, precision medicine technologies enable a proactive approach to ADRs and support clinicians to change prescribing accordingly. This commentary revisits the famous pharmacology–toxicology continuum first postulated by Paracelsus 500 years ago and explains why precision dosing is needed to help avoid ADRs in modern clinical practice. Strategies on how to improve precision dosing are given, including more research to establish better precision dosing targets in the cases of greatest need, easier access to dosing instructions via e-prescribing, improved monitoring of patients with novel biomarkers of drug response, and further application of model-informed precision dosing.
Publisher: Wiley
Date: 27-06-2012
Publisher: Oxford University Press (OUP)
Date: 27-04-2009
DOI: 10.1093/JAC/DKP139
Abstract: To compare the plasma and subcutaneous tissue concentration-time profiles of meropenem administered by intermittent bolus dosing or continuous infusion to critically ill patients with sepsis and without renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the cumulative fraction of response (CFR) against Gram-negative pathogens likely to be encountered in critical care units. We randomized 10 patients with sepsis to receive meropenem by intermittent bolus administration (n = 5 1 g 8 hourly) or an equal dose administered by continuous infusion (n = 5). Serial subcutaneous tissue concentrations were determined using microdialysis and compared with plasma data for first-dose and steady-state pharmacokinetics. Population pharmacokinetic modelling of plasma data and Monte Carlo simulations were then undertaken with NONMEM. It was found that continuous infusion maintains higher median trough concentrations, in both plasma (intermittent bolus 0 versus infusion 7 mg/L) and subcutaneous tissue (0 versus 4 mg/L). All simulated intermittent bolus, extended and continuous infusion dosing achieved 100% of pharmacodynamic targets against most Gram-negative pathogens. Superior obtainment of pharmacodynamic targets was achieved using administration by extended or continuous infusion against less susceptible Pseudomonas aeruginosa and Acinetobacter species. This is the first study to compare the relative concentration-time data of bolus and continuous administration of meropenem at the subcutaneous tissue and plasma levels. We found that the administration of meropenem by continuous infusion maintains higher concentrations in subcutaneous tissue and plasma than by intermittent bolus dosing. Administration by extended or continuous infusion will achieve superior CFR against less-susceptible organisms in patients without renal dysfunction.
Publisher: Oxford University Press (OUP)
Date: 11-09-2018
DOI: 10.1093/JAC/DKY371
Abstract: To develop a population pharmacokinetic (PK) model for vancomycin in adults receiving high-flux haemodialysis (HFHD) in an effort to optimize vancomycin dosing in this population. A population PK model using NONMEM was developed using retrospective data collected from 48 vancomycin courses administered to patients (n = 37) receiving HFHD. Fixed-dose [1.5 g loading dose (LD), 1 g maintenance dose (MD)], literature-adapted weight-based (WBL 20 mg/kg LD, 10 mg/kg MD) and hospital-adapted weight-based (WBH 25-30 mg/kg LD, 20-25 mg/kg MD) dosage regimens were then simulated using the Monte Carlo method. The PTA was an AUC24/MIC ≥400 with success being a PTA ≥90%. The data were best described using a two-compartment model. It was observed that fixed-dose and WBL dosage regimens resulted in a PTA ≤90% for most days. The WBH dosing achieved a PTA ≥90% on most days, but there were supratherapeutic concentrations with repeated dosing of vancomycin. If HFHD was delayed by 48-72 h after the LD, the PTA would fall below 90%. A dose-optimized regimen was developed: 30 mg/kg LD and 10 mg/kg MD given on HFHD days. An additional dose of 500 mg or 1 g was administered 24 h after the LD if HFHD occurred 48-72 h post-LD. This dose-optimized regimen afforded a PTA ≥90% on all days of therapy and achieved clinically acceptable pre-haemodialysis concentrations. Current vancomycin dosage regimens used clinically do not achieve a PTA ≥90% for most days of therapy for people receiving HFHD. A dose-optimized regimen was developed, which could be implemented in clinical practice.
Publisher: Elsevier BV
Date: 2002
DOI: 10.1016/S0378-4347(01)00430-3
Abstract: A rapid and simple high-performance liquid chromatographic (HPLC) assay for the determination of metformin in human plasma and breast milk is described. After proteins were precipitated with acetonitrile, metformin and the internal standard buformin were resolved on a cation-exchange column and detected by UV detection at 236 nm. Standard curves were linear over the concentration range 20.0-4000 microg/l. Intra- and inter-day coefficients of variation were <9.0% and the limit of quantification was around 20 microg/l.
Publisher: Wiley
Date: 1999
DOI: 10.1046/J.1365-2125.1999.00850.X
Abstract: To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents. Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring were reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, in idualisation of therapy, s ling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring. There is a strong historical case for monitoring aminoglycosides. The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances. The approach to monitoring aminoglycosides needs to be redefined in the light of once-daily dosing. It is premature to suggest that less stringent monitoring is necessary as toxicity remains a problem with these drugs. The ideal method of monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is monitored occasionally to ensure efficacy while flucytosine is monitored occasionally to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.
Publisher: Frontiers Media SA
Date: 27-10-2022
DOI: 10.3389/FIMMU.2022.1022104
Abstract: Bronchopulmonary dysplasia (BPD), its complication pulmonary hypertension (BPD-PH) and preterm brain and gut injury lead to significant morbidity and mortality in infants born extremely prematurely. There is extensive evidence that the pro-inflammatory cytokine interleukin 1 (IL-1) plays a key role in the pathophysiology of these illnesses. Two decades of clinical use in paediatric and adult medicine have established an excellent safety and efficacy record for IL-1 blockade with IL-1 receptor antagonist (IL-1Ra, medication name anakinra). Building on robust pre-clinical evidence, the Anakinra Pilot trial aims to demonstrate safety and feasibility of administering anakinra to preterm infants, and to establish pharmacokinetics in this population. Its ultimate goal is to facilitate large studies that will test whether anakinra can ameliorate early-life inflammation, thus alleviating multiple complications of prematurity. Anakinra Pilot is an investigator-initiated, single arm, safety and feasibility dose-escalation trial in extremely preterm infants born between 24 weeks 0 days (24 0 ) and 27 6 weeks of gestational age (GA). Enrolled infants will receive anakinra intravenously over the first 21 days after birth, starting in the first 24 h after birth. In the first phase, dosing is 1 mg/kg every 48 h, and dosage will increase to 1.5 mg/kg every 24 h in the second phase. Initial anakinra dosing was determined through population pharmacokinetic model simulations. During the study, there will be a interim analysis to confirm predictions before undertaking dose assessment. Anakinra therapy will be considered safe if the frequency of adverse outcomes/events does not exceed that expected in infants born at 24 0 -27 6 weeks GA. clinicaltrials.gov/ , identifier NCT05280340.
Publisher: Wiley
Date: 09-2015
DOI: 10.1002/JPPR.1121
Publisher: SAGE Publications
Date: 26-11-2016
Abstract: The objective of our study was to describe spontaneously reported haemorrhagic adverse events associated with rivaroxaban and dabigatran in Australia. Data were sourced from the Australian Therapeutic Goods Administration (TGA) Database of Adverse Event Notifications between June 2009 and May 2014. Records of haemorrhagic adverse events in which rivaroxaban or dabigatran was considered as a potential cause were analysed. There were 240 haemorrhagic adverse events associated with rivaroxaban and 504 associated with dabigatran. Age was specified for 164 (68%) haemorrhages associated with rivaroxaban, of which 101 occurred in people aged ⩾75 years. Age was specified for 437 (87%) haemorrhages associated with dabigatran, of which 300 occurred in people aged ⩾75 years. Time from treatment initiation to haemorrhage was specified for 122 (51%) haemorrhages associated with rivaroxaban, with 69 (57%) haemorrhages occurring within 30 days of rivaroxaban initiation. Time from treatment initiation to haemorrhage was specified for 253 (50%) haemorrhages associated with dabigatran, with 123 (49%) haemorrhages occurring within 30 days of dabigatran initiation. Gastrointestinal (GI) haemorrhages were the most frequent type of haemorrhages associated with both rivaroxaban ( n = 105, 44%) and dabigatran ( n = 302, 60%). Data were available on the severity of haemorrhage for 101 (42%) haemorrhages associated with rivaroxaban, with haemorrhage leading to death in 17 people. The severity of haemorrhage was specified for 384 (76%) haemorrhages associated with dabigatran, with haemorrhage leading to death in 61 people. Our study highlights the need for research on the haemorrhagic complications of anticoagulation in clinical care. A considerable proportion of reported haemorrhagic events occurred within 30 days of rivaroxaban and dabigatran initiation. This highlights the importance of considering bleeding risk at the time of treatment initiation.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JCJQ.2019.03.001
Abstract: Medical emergency teams (METs) rescue deteriorating patients as the response arm of hospital rapid response systems. This study aimed to (1) investigate medication use during MET activations by describing the type, frequency and access sources of medications and (2) assess associations between patient characteristics, MET activation criteria, and outcomes and MET medication use. A single-center, retrospective study from a prospective database of MET activations in an Australian tertiary referral hospital was undertaken. Consecutive adult MET activations over a 12-month period were included. Across the study period, there were 5,727 MET activations with medications used at 33.5% (n = 1,920). Of 2,648 medications used, cardiac system agents (n = 944 35.6%) were the most common category used, while intravenous electrolytes (n = 341 12.9%) and opioid analgesics (n = 248 9.4%).were the most frequently used medications. Most commonly, medications were sourced from ward stocks. High blood pressure, heart or respiratory rate, pain, and multiple activation criteria were associated with MET medication use (p < 0.001). Patients who required medications were less likely to remain on the ward, and immediate admission to the ICU was approximately doubled (odds ratio = 1.90 95% confidence interval = 1.47-2.45). Medication use by the MET was common and associated with escalation to intensive care. A wide variety of medications, principally from ward stocks, were used with some predictability based on activation criteria. Local system improvements have demonstrated that by focusing on common MET syndromes and medications, further investigation can refine and improve medication use and management systems for deteriorating patients.
Publisher: Wiley
Date: 03-04-2008
Publisher: Oxford University Press (OUP)
Date: 29-10-2019
DOI: 10.1093/JAC/DKY415
Abstract: Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC50 = 1.79 μM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.
Publisher: Springer Science and Business Media LLC
Date: 14-02-2014
DOI: 10.1007/S00228-014-1652-7
Abstract: Frailty, a multifactorial biological syndrome characterized by a cumulative dysregulation of physiological processes, is associated with changes in pharmacokinetics and pharmacodynamics. The aim of this study was to quantify the effect of frailty on glomerular filtration of drugs, using the probe drug gentamicin. Gentamicin concentrations and clinical data including the Reported Edmonton Frail Scale score were pooled from two prospective observational inpatient studies, one on prophylactic gentamicin for urologic surgery and one on therapeutic gentamicin for the empiric treatment of sepsis. Population pharmacokinetic modeling was performed using non-linear mixed effects modeling (NONMEM program) to determine the impact of frailty on gentamicin clearance. A one-compartment linear pharmacokinetic model best described the data and the addition of frailty to the model reduced the random variability in gentamicin clearance by 12 % after adjustment for renal function (estimated creatinine clearance using lean body weight) and lean body weight. Frail patients had an approximately 12 % lower (bootstrapping results: 14 % median) gentamicin clearance than non-frail patients (calculated as a fractional effect of frailty). Frailty may independently predict reduced clearance of gentamicin in older patients. Frailty could be considered in the development of dosing guidelines for drugs that undergo significant excretion through glomerular filtration.
Publisher: Wiley
Date: 31-08-2020
Publisher: MDPI AG
Date: 06-10-2022
Abstract: SARS-CoV-2 is the cause of the COVID-19 pandemic which has claimed more than 6.5 million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14,000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA-approved molecules with established safety profiles that have plausible mechanisms for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising drug candidates that can be repurposed for the safe, efficacious, and cost-effective treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx that was also developed to enable the scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2018
DOI: 10.1007/S00702-018-1922-0
Abstract: Common polymorphisms in the genes encoding CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes have an important role in predicting the occurrence of adverse effects and the efficacy of substrate medications. Drug-induced changes to the enzyme's phenotype, a process called phenoconversion, comprise another important factor contributing to interin idual variability in drug response. To date, there is lack of data on the frequency of these common polymorphisms and phenoconversion in the pan-ethnic Australian population. The aim of this study was to (1) describe allele, genotype and phenotype frequencies for CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes in the pan-ethnic Australian population and (2) evaluate the frequency of actionable pharmacogenomic (PGx) variants and phenoconversion. Frequencies were calculated using the records of 5408 Australian patients (obtained from myDNA's propriety database), who were consecutively tested with the DNAdose PGx test which included the CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes. In 2509 patients with listed medications at the time of testing, phenoconversion frequencies were calculated for CYP2D6, CYP2C19 and CYP2C9 enzymes. Allele, genotype and phenotype frequencies in our Australian patients correlated with a Caucasian population. Approximately 96% of patients had at least one actionable PGx variant. A five-fold increase in the frequency of poor metabolisers (PMs) for CYP2D6 and CYP2C19 was predicted by phenoconversion. Our study results indicate a high frequency of actionable PGx variants in our Australian population. With the addition of drug-induced phenoconversion, our results provide further support for the utilisation of PGx testing in clinical practice as another tool assisting prescribers in the application of personalised medicine.
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.JAMDA.2015.03.003
Abstract: The objective of the study was to investigate the prevalence of, and factors associated with, polypharmacy in long-term care facilities (LTCFs). MEDLINE, EMBASE, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library were searched from January 2000 to September 2014. Primary research studies in English were eligible for inclusion if they fulfilled the following criteria: (1) polypharmacy was quantitatively defined, (2) the prevalence of polypharmacy was reported or could be extracted from tables or figures, and (3) the study was conducted in a LTCF. Methodological quality was assessed using an adapted version of the Joanna Briggs Institute Critical Appraisal Checklist. Forty-four studies met the inclusion criteria and were included. Polypharmacy was most often defined as 5 or more (n = 11 studies), 9 (n = 13), or 10 (n = 11) medications. Prevalence varied widely between studies, with up to 91%, 74%, and 65% of residents taking more than 5, 9, and 10 medications, respectively. Seven studies performed multivariate analyses for factors associated with polypharmacy. Positive associations were found for recent hospital discharge (n = 2 studies), number of prescribers (n = 2), and comorbidity including circulatory diseases (n = 3), endocrine and metabolic disorders (n = 3), and neurological motor dysfunctioning (n = 3). Older age (n = 5), cognitive impairment (n = 3), disability in activities of daily living (n = 3), and length of stay in the LTCF (n = 3) were inversely associated with polypharmacy. The prevalence of polypharmacy in LTCFs is high, varying widely between facilities, geographical locations and the definitions used. Greater use of multivariate analysis to investigate factors associated with polypharmacy across a range of settings is required. Longitudinal research is needed to explore how polypharmacy has evolved over time.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.CGH.2014.02.024
Abstract: Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD. Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were randomly assigned to groups given 3000 mg resveratrol (n = 10) or placebo (n = 10) daily for 8 weeks. Outcomes included insulin resistance (assessed by the euglycemic-hyperinsulinemic cl ), hepatic steatosis, and abdominal fat distribution (assessed by magnetic resonance spectroscopy and imaging). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed. Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1, PTP1B, IL6, or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated. Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.
Publisher: Wiley
Date: 18-05-2022
DOI: 10.1002/CPT.2618
Abstract: Dosing guidance for children with obesity is often unknown despite the fact that nearly 20% of US children are classified as obese. Enoxaparin, a commonly prescribed low‐molecular‐weight heparin, is dosed based on body weight irrespective of obesity status to achieve maximum concentration within a narrow therapeutic or prophylactic target range. However, whether children with and without obesity experience equivalent enoxaparin exposure remains unclear. To address this clinical question, 2,825 anti–activated factor X (anti‐Xa) surrogate concentrations were collected from the electronic health records of 596 children, including those with obesity. Using linear mixed‐effects regression models, we observed that 4‐hour anti‐Xa concentrations were statistically significantly different in children with and without obesity, even for children with the same absolute dose ( P = 0.004). To further mechanistically explore obesity‐associated differences in anti‐Xa concentration, a pediatric physiologically‐based pharmacokinetic (PBPK) model was developed in adults, and then scaled to children with and without obesity. This PBPK model incorporated binding of enoxaparin to antithrombin to form anti‐Xa and elimination via heparinase‐mediated metabolism and glomerular filtration. Following scaling, the PBPK model predicted real‐world pediatric concentrations well, with an average fold error (standard deviation of the fold error) of 0.82 (0.23) and 0.87 (0.26) in children with and without obesity, respectively. PBPK model simulations revealed that children with obesity have at most 20% higher 4‐hour anti‐Xa concentrations under recommended, total body weight–based dosing compared to children without obesity owing to reduced weight‐normalized clearance. Enoxaparin exposure was better matched across age groups and obesity status using fat‐free mass weight‐based dosing.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.AUCC.2018.05.006
Abstract: In hospitals, rapid response systems (RRSs) identify patients who deteriorate and provide critical care at their bedsides to stabilise and escalate care. Medications, including oral and parenteral pharmaceutical preparations, are the most common intervention for hospitalised patients and the most common cause of harm. This connection between clinical deterioration and medication safety is poorly understood. To inform improvements in prevention and management of clinical deterioration, this review aimed to examine how medications contributed to clinical deterioration and how medications were used in RRSs. A scoping review was undertaken of medication data reported in studies of clinical deterioration or RRSs in erse hospital settings between 2005 and 2017. Bibliographic database searches used permutations of "rapid response system," "medical emergency team," and keyword searching with medication-related terms. Independent selection, quality assessment, and data extraction informed mapping against four medication themes: causes of deterioration, predictors of deterioration, RRS use, and management. Thirty articles were reviewed. Quality was low: limited by small s les, observational, single-centre designs and few primary medication-related outcomes. Adverse drug reactions and potentially preventable medication errors, involving sedatives, analgesics, and cardiovascular agents, contributed to clinical deterioration. While sparsely reported, outcomes included death and escalation of care. In children, administration of antibiotics or nebulised medications appeared to predict subsequent deterioration. Cardiovascular medications, sedatives, and analgesics commonly were used to manage deterioration but further detail was lacking. Despite reported potential for patient harm, evaluation of medication management systems was limited. Medications contributed to potentially preventable clinical deterioration, with considerable harm, and were common interventions for its management. When assessing deteriorating patients or caring for patients who require escalation to critical care, clinicians should consider medication errors and adverse reactions. Studies with more specific medication-related, patient-centred end points could reduce medication-related deterioration and refine RRS medication use and management.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2013
Publisher: Wiley
Date: 09-06-2011
Publisher: Informa UK Limited
Date: 28-12-2004
Abstract: The aim of this report is to describe the use of WinBUGS for two datasets that arise from typical population pharmacokinetic studies. The first dataset relates to gentamicin concentration-time data that arose as part of routine clinical care of 55 neonates. The second dataset incorporated data from 96 patients receiving enoxaparin. Both datasets were originally analyzed by using NONMEM. In the first instance, although NONMEM provided reasonable estimates of the fixed effects parameters it was unable to provide satisfactory estimates of the between-subject variance. In the second instance, the use of NONMEM resulted in the development of a successful model, albeit with limited available information on the between-subject variability of the pharmacokinetic parameters. WinBUGS was used to develop a model for both of these datasets. Model comparison for the enoxaparin dataset was performed by using the posterior distribution of the log-likelihood and a posterior predictive check. The use of WinBUGS supported the same structural models tried in NONMEM. For the gentamicin dataset a one-compartment model with intravenous infusion was developed, and the population parameters including the full between-subject variance-covariance matrix were available. Analysis of the enoxaparin dataset supported a two compartment model as superior to the one-compartment model, based on the posterior predictive check. Again, the full between-subject variance-covariance matrix parameters were available. Fully Bayesian approaches using MCMC methods, via WinBUGS, can offer added value for analysis of population pharmacokinetic data.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2016
DOI: 10.1213/ANE.0000000000001463
Abstract: We compared plasma and cerebrospinal fluid (CSF) pharmacokinetics of paracetamol after intravenous (IV) and oral administration to determine dosing regimens that optimize CSF concentrations. Twenty-one adult patients were assigned randomly to 1 g IV, 1 g oral or 1.5 g oral paracetamol. An IV cannula and lumbar intrathecal catheter were used to s le venous blood and CSF, respectively, over 6 hours. The plasma and CSF maximum concentrations ( C max ), times to maximum concentrations ( T max ), and area under the plasma and CSF concentration-time curves (AUCs) were calculated using noncompartmental techniques. Significance was defined by P .0167 (Bonferroni correction for 3 comparisons for each parameter). Probability (X Y) ( p ″) with Bonferroni corrected 95% confidence intervals (CIs) were calculated (CIs including 0.5 meet the null hypothesis). Results are presented as median (range) or p ″ (CI). P values are listed as 1 g IV vs 1 g orally, 1 g IV vs 1.5 g orally and 1 g orally vs 1.5 g orally, respectively. Wide variation in measured paracetamol concentrations was observed, especially in the oral groups. The median plasma C max in the 1 g IV group was significantly greater than the oral groups. In contrast, the median CSF C max was not different between groups. The median plasma T max in the 1 g IV group was 105 and 75 minutes earlier than in the 1 and 1.5 g oral groups. The median CSF T max was not significantly different between groups. The median plasma AUC (total) was not significantly different between groups however, in the first hour, the median plasma AUC was significantly greater in the IV group than in the oral groups. In the second hour, there was no difference between groups. The median CSF AUC (total) did not significantly differ between groups however, in the first hour, the median CSF AUC was significantly greater in the IV compared with the orally groups. In the second hour, there was no difference between groups. Our analysis indicated that the median C max , T max , and AUC values lacked precision because of small s le sizes. Peak plasma concentrations were greater and reached earlier after IV than oral dosing. Evidence for differences in CSF C max and T max was lacking because of the small size of this study.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.CRITREVONC.2022.103606
Abstract: Palifermin, a recombinant keratinocyte growth factor promotes thickening of the mucosa, minimising severity of mucositis caused by chemotherapy and radiotherapy. To synthesise published literature on palifermin for the management of oral mucositis, in patients receiving chemotherapy and/or radiotherapy, aiming to ascertain recommendations for practice. Databases searched were Medline, Embase, IPA and CIANHL. A meta-analysis included randomised controlled trials (RCT) for palifermin compared to placebo or no palifermin, with the key data extracted being number of events of severe mucositis (defined by WHO criteria grade 3 or 4). The meta-analysis included 10 RCT. Patients were treated for solid and haematological malignancy. Analysis suggested benefit of palifermin decreasing the incidence of severe mucositis in solid tumours RR0.76 [95%CI 0.63-0.92 = 0.004], haematological malignancy RR0.63 [95 %CI 0.48-0.82 = 0.0007] and overall RR0.69 [95 %CI 0.59-0.81 < 0.0001]. Palifermin reduces the incidence of severe mucositis up to 30 % in patients receiving treatment with chemotherapy and/or radiotherapy.
Publisher: Springer Science and Business Media LLC
Date: 06-11-2017
Publisher: Future Medicine Ltd
Date: 10-2022
Abstract: Pharmacogenomic (PGx) testing of cytochrome P450 (CYP) enzymes may improve the efficacy and/or safety of some medications. This is facilitated by increased availability and affordability of genotyping, the development of clinical practice PGx guidelines and regulatory support. However, the common occurrence of CYP phenoconversion, a mismatch between genotype-predicted CYP phenotype and the actual CYP phenotype, currently limits the application of PGx testing for precision dosing in psychiatry. This review proposes a stepwise approach to assist precision dosing in psychiatry via the introduction of PGx stewardship programs and innovative PGx education strategies. A future perspective on delivering precision dosing for psychiatrists is discussed that involves innovative clinical decision support systems powered by model-informed precision dosing.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.DIAGMICROBIO.2017.12.019
Abstract: We described bacterial killing and resistance emergence at various fixed concentrations of meropenem and piperacillin/tazobactam against Pseudomonas aeruginosa and Escherichia coli. Time-kill studies were conducted utilizing nine isolates and a large range of concentrations. Within each strain and antibiotic, initial killing was similar, with concentrations ≥2×MIC. At many (strain-specific) concentrations causing substantial initial killing, regrowth occurred at 24-48h. For remaining concentrations, growth typically remained suppressed (<5-log
Publisher: Informa UK Limited
Date: 25-09-2015
Publisher: Springer Science and Business Media LLC
Date: 2023
Publisher: Springer Science and Business Media LLC
Date: 2003
DOI: 10.2165/00003088-200342140-00002
Abstract: Drugs and metabolites are eliminated from the body by metabolism and excretion. The kidney makes the major contribution to excretion of unchanged drug and also to excretion of metabolites. Net renal excretion is a combination of three processes - glomerular filtration, tubular secretion and tubular reabsorption. Renal function has traditionally been determined by measuring plasma creatinine and estimating creatinine clearance. However, estimated creatinine clearance measures only glomerular filtration with a small contribution from active secretion. There is accumulating evidence of poor correlation between estimated creatinine clearance and renal drug clearance in different clinical settings, challenging the 'intact nephron hypothesis' and suggesting that renal drug handling pathways may not decline in parallel. Furthermore, it is evident that renal drug handling is altered to a clinically significant extent in a number of disease states, necessitating dosage adjustment not just based on filtration. These observations suggest that a re-evaluation of markers of renal function is required. Methods that measure all renal handling pathways would allow informed dosage in idualisation using an understanding of renal excretion pathways and patient characteristics. Methodologies have been described to determine in idually each of the renal elimination pathways. However, their simultaneous assessment has only recently been investigated. A cocktail of markers to measure simultaneously the in idual renal handling pathways have now been developed, and evaluated in healthy volunteers. This review outlines the different renal elimination pathways and the possible markers that can be used for their measurement. Diseases and other physiological conditions causing altered renal drug elimination are presented, and the potential application of a cocktail of markers for the simultaneous measurement of drug handling is evaluated. Further investigation of the effects of disease processes on renal drug handling should include people with HIV infection, transplant recipients (renal and liver) and people with rheumatoid arthritis. Furthermore, changes in renal function in the elderly, the effect of sex on renal function, assessment of living kidney donors prior to transplantation and the investigation of renal drug interactions would also be potential applications. Once renal drug handling pathways are characterised in a patient population, the implications for accurate dosage in idualisation can be assessed. The simultaneous measurement of renal function elimination pathways of drugs and metabolites has the potential to assist in understanding how renal function changes with different disease states or physiological conditions. In addition, it will further our understanding of fundamental aspects of the renal elimination of drugs.
Publisher: Wiley
Date: 15-01-2021
DOI: 10.1111/BCP.14718
Abstract: We propose the use of in silico mathematical models to provide insights that optimize therapeutic interventions designed to effectively treat respiratory infection during a pandemic. A modelling and simulation framework is provided using SARS‐CoV‐2 as an ex le, considering applications for both treatment and prophylaxis. A target cell‐limited model was used to quantify the viral infection dynamics of SARS‐CoV‐2 in a pooled population of 105 infected patients. Parameter estimates from the resulting model were used to simulate and compare the impact of various interventions against meaningful viral load endpoints. Robust parameter estimates were obtained for the basic reproduction number, viral release rate and infected‐cell mortality from the infection model. These estimates were informed by the largest dataset currently available for SARS‐CoV‐2 viral time course. The utility of this model was demonstrated using simulations, which hypothetically introduced inhibitory or stimulatory drug mechanisms at various target sites within the viral life‐cycle. We show that early intervention is crucial to achieving therapeutic benefit when monotherapy is administered. In contrast, combination regimens of two or three drugs may provide improved outcomes if treatment is initiated late. The latter is relevant to SARS‐CoV‐2, where the period between infection and symptom onset is relatively long. The use of in silico models can provide viral load predictions that can rationalize therapeutic strategies against an emerging viral pathogen.
Publisher: Wiley
Date: 08-11-2008
Publisher: Oxford University Press (OUP)
Date: 18-05-2012
DOI: 10.1111/J.2042-7174.2012.00210.X
Abstract: To review current literature with the objective of developing strategies and recommendations to enhance patient safety and minimise clinical issues with look-alike, sound-alike medication names. A comprehensive search of the PubMed database and an Australian online repository of Quality Use of Medicines projects was conducted to identify publications addressing look-alike, sound-alike medication problems. Author networks, grey literature and the reference lists of published articles were also used to identify additional material. Thirty-two publications describing the extent of the specific problem and recommending solutions were identified. The majority of these publications provided a qualitative assessment of the issues, with few quantitative estimates of the severity of the problem and very little intervention research. As a result, most recommendations for addressing the problem are the result of expert deliberations and not experimental research. This will affect the capacity of the recommendations to ameliorate and resolve problems caused by look-alike, sound-alike medication names. Themes identified from articles included the nature and causes of look-alike, sound-alike problems, potential solutions and recommendations. There are many existing medications which can potentially cause clinical issues due to mix-ups because of similar sounding or looking medication names. This confusion can be lethal for some medication errors. A multifaceted, integrated approach involving all aspects of the medication use process, from initial naming of INN through to consumer education, is suggested to minimise this issue for medication safety.
Publisher: Wiley
Date: 20-02-2017
DOI: 10.1111/BCP.13229
Publisher: Springer Science and Business Media LLC
Date: 02-2011
DOI: 10.2165/11534750-000000000-00000
Abstract: Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine. Metformin is excreted unchanged in urine. The elimination half-life (t(½ )) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CL(R)) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CL(R) and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CL(CR)). As the CL(R) and CL/F decrease approximately in proportion to CL(CR), the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CL(CR). The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin. Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5 mg/L in order to minimize the development of this adverse effect.
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1186/S13054-015-0750-Y
Abstract: The aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic harmacodynamic (PK/PD) target attainment (time above MIC ( f T MIC )) in critically ill patients with sepsis receiving intermittent dosing. To be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood s les were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CL CR ). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% f T MIC was calculated for varying MIC and CL CR values. In total, 48 patients provided data. Increasing CL CR values were associated with lower trough plasma piperacillin concentrations ( P 0.01), such that with an MIC of 16 mg/L, 100% f T MIC would be achieved in only one-third ( n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CL CR ( r = 0.58, P 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% f T MIC , was noted with increasing CL CR measures. Standard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CL CR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2013
DOI: 10.1007/S40262-013-0046-9
Abstract: Metformin is contraindicated in patients with renal impairment however, there is poor adherence to current dosing guidelines. In addition, the pharmacokinetics of metformin in patients with significant renal impairment are not well described. The aims of this study were to investigate factors influencing the pharmacokinetic variability, including variant transporters, between healthy subjects and patients with type 2 diabetes mellitus (T2DM) and to simulate doses of metformin at varying stages of renal function. Plasma concentrations of metformin were pooled from three studies: patients with T2DM (study A n = 120), healthy Caucasian subjects (study B n = 16) and healthy Malaysian subjects (study C n = 169). A population pharmacokinetic model of metformin was developed using NONMEM(®) version VI for both the immediate-release (IR) formulation and the extended-release (XR) formulation of metformin. Total body weight (TBW), lean body weight (LBW), creatinine clearance (CLCR estimated using TBW and LBW) and 57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT) were investigated as potential covariates. A nonparametric bootstrap (n = 1,000) was used to evaluate the final model. This model was used to simulate 1,000 concentration-time profiles for doses of metformin at each stage of renal impairment to ensure metformin concentrations do not exceed 5 mg/l, the proposed upper limit. Creatinine clearance and TBW were clinically and statistically significant covariates with the apparent clearance and volume of distribution of metformin, respectively. None of the 57 SNPs in transporters of metformin were significant covariates. In contrast to previous studies, there was no effect on the pharmacokinetics of metformin in patients carrying the reduced function OCT1 allele (R61C, G401S, 420del or G465R). Dosing simulations revealed that the maximum daily doses in relation to creatinine clearance to prescribe to patients are 500 mg (15 ml/min), 1,000 mg (30 ml/min), 2,000 mg (60 ml/min) and 3,000 mg (120 ml/min), for both the IR and XR formulations. The population model enabled doses of metformin to be simulated for each stage of renal function, to ensure the concentrations of metformin do not exceed 5 mg/l. However, the plasma concentrations of metformin at these dosage levels are still quite variable and monitoring metformin concentrations may be of value in in idualising dosage. This study provides confirmatory data that metformin can be used, with appropriate dosage adjustment, in patients with renal impairment.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.IJANTIMICAG.2017.12.017
Abstract: The aim of this study was to systematically evaluate whether non-weight-based dosing (non-WBD) or weight-based dosing (WBD) of vancomycin leads to a higher proportion of patients achieving the pharmacokinetic harmacodynamic target. Studies from January 1985 to February 2017 were identified through Cochrane, MEDLINE and Embase databases. Those conducted in adults with end-stage renal disease receiving high-flux haemodialysis (HD) and intravenous vancomycin were included. The primary outcome was the proportion of patients with a pre-HD vancomycin concentration of 15-20 mg/L and/or an area under the concentration-time curve/minimum inhibitory concentration (AUC/MIC) ratio ≥400. Of the 3948 studies screened, 5 met the inclusion criteria. The proportion of patients with pre-HD concentrations between 15-20 mg/L were 35% (non-WBD) and 13% (WBD) post-loading dose. During maintenance dosing, the proportion of patients with pre-HD concentrations between 15-20 mg/L were 37% (non-WBD) and 50-67% (WBD). The proportion of pre-HD concentrations <15 mg/L was greater in the non-WBD group post-loading dose but was similar between the non-WBD and WBD group during maintenance dosing. One study reported that all patients had an AUC/MIC ≥ 400 for micro-organisms with an MIC ≤ 1 mg/L for weight-based maintenance dosing. The limited data suggest that WBD may be preferential as there was a smaller proportion of pre-HD concentrations falling below 15 mg/L. However, larger well-designed studies of higher quality are required to provide guidance for vancomycin dosing in the high-flux HD setting. Future research should focus on reporting AUC/MIC ratios and exploring clinical outcomes in this patient population.
Publisher: SAGE Publications
Date: 2015
DOI: 10.1186/S40697-015-0066-5
Abstract: Erythropoiesis stimulating agent (ESA)-resistant anemia is common in chronic kidney disease (CKD). To evaluate the determinants of severity of ESA resistance in patients with CKD and primary ESA-resistance. Secondary analysis of a randomized controlled trial (the Handling Erythropoietin Resistance with Oxpentifylline, HERO) 53 adult patients with CKD stage 4 or 5 and primary ESA-resistant anemia (hemoglobin ≤120 g/L, ESA resistance index [ERI] ≥1.0 IU/kg/week/gHb for erythropoietin or ≥0.005 μg/kg/week/gHb for darbepoeitin, no cause for ESA-resistance identified). Iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation. Participants were ided into tertiles of ERI. Multinomial logistic regression was used to analyse the determinants of ERI tertiles. All patients, except one, were receiving dialysis for end-stage kidney disease. The mean ± SD ERI values in the low ( n = 18), medium ( n = 18) and high ( n = 17) ERI tertiles were 1.4 ± 0.3, 2.3 ± 0.2 and 3.5 ± 0.8 IU/kg/week/gHb, respectively ( P 0.001). There were no significant differences observed in age, gender, ethnicity, cause of kidney disease, diabetes, iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation between the ERI tertiles. The median [inter-quartile range] serum alkaline phosphatase concentrations in the low, medium and high ERI tertiles were 89 [64,121], 99 [76,134 and 148 [87,175] U/L, respectively ( P = 0.054). There was a weak but statistically significant association between ERI and serum alkaline phosphatase (R 2 = 0.06, P = 0.03). Using multinomial logistic regression, the risk of being in the high ERI tertile relative to the low ERI tertile increased with increasing serum alkaline phosphatase levels ( P = 0.02). No other variables were significantly associated with ERI. Small s le size bone-specific alkaline phosphatase, other markers of bone turnover and bone biopsies not evaluated. Serum alkaline phosphatase was associated with severity of ESA resistance in ESA-resistant patients with CKD. Large prospective studies are required to confirm this association. (Trial registration: Australian New Zealand Clinical Trials Registry 12608000199314)
Publisher: Oxford University Press (OUP)
Date: 04-03-2021
Abstract: Frail older people have a high prevalence of drug use and are susceptible to adverse drug reactions. The physiological changes of frailty are likely to affect pharmacokinetics and pharmacodynamics. We reviewed the methods and findings of published studies of pharmacokinetics in frailty. Nine studies describing pharmacokinetics and an additional three of pharmacokinetic pathways in frail older people were identified. Most pharmacokinetic studies investigated a single administration of a medication, dose or formulation, in small populations, often with limited representation of males or females, and applied variable definitions of frailty. Pharmacokinetic s ling designs generally utilised saturated s ling followed by analysis based on the trapezoidal rule for area under the curve, with more recent studies using sparser s ling and more sophisticated modelling to obtain in idual and population values of all pharmacokinetic parameters. Overall, the pharmacokinetic studies reported only small changes in some parameters for some drugs with frailty, with the most consistent change reduced hepatic clearance in frail older people. Recommendations for future studies of pharmacokinetics in frailty include (i) standard objective definitions of frailty (ii) larger studies including people with mild, moderate and severe frailty (iii) population pharmacokinetic modelling to allow sparser s ling and consideration of multiple influences on pharmacokinetics (iv) physiologically based modelling as the physiology of frailty emerges and (v) longitudinal pharmacokinetic studies of chronic drug therapy from middle to old age and from robust to pre-frail to frail, including pre-clinical studies. These data, accompanied by pharmacodynamics data in frailty, will inform safe, effective prescribing for frail older people.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2003
DOI: 10.1097/00007691-200310000-00012
Abstract: A retrospective review was undertaken in 744 patients who were dose-in idualized with gentamicin once daily to evaluate a change in gentamicin clearance as a potential predictor of nephrotoxicity. The definition of nephrotoxicity was chosen to be a change in creatinine clearance greater than 20%. Similarly, a change in gentamicin clearance of greater than 20% was also considered a possible index of nephrotoxicity. Four criteria were developed to assess the usefulness of gentamicin clearance as a predictor of nephrotoxicity. Following the application of the inclusion/exclusion criteria, 132 patients were available for the analysis. The sensitivity, specificity, positive predictive value, and negative predictive value were assessed for each of the criteria. Receiver operating characteristic (ROC) curves were produced to determine if an optimum value in the change of gentamicin clearance could be found to maximize sensitivity and specificity. The overall incidence of nephrotoxicity based on a decrease in creatinine clearance by 20% or more was 3.8%. Women were overrepresented in the nephrotoxic group [71.4% versus 40.1% (P = 0.0025)]. Patients with nephrotoxicity had statistically longer treatment periods, increased cumulative dose, and more dosing predictions (P < 0.05 in each case). The sensitivity of the criteria ranged from 43 to 46%, and specificity ranged from 93 to 99%. The positive and negative predictive values ranged from 63 to 94% and 86 to 89%, respectively. In those patients in whom nephrotoxicity was predicted from a change in gentamicin clearance, this change occurred on average 3 days before the change in creatinine clearance (P < 0.05). A change in gentamicin clearance to predict nephrotoxicity may be a useful addition to current monitoring methods, although it is not the complete answer.
Publisher: American Society for Microbiology
Date: 20-12-2019
DOI: 10.1128/AAC.01679-19
Abstract: Augmented renal clearance (ARC) is common in critically ill patients and is associated with subtherapeutic concentrations of renally eliminated antibiotics. We investigated the impact of ARC on bacterial killing and resistance lification for meropenem and tobramycin regimens in monotherapy and combination. Two carbapenem-resistant Pseudomonas aeruginosa isolates were studied in static-concentration time-kill studies. One isolate was examined comprehensively in a 7-day hollow-fiber infection model (HFIM).
Publisher: Public Library of Science (PLoS)
Date: 07-2015
Publisher: Springer Science and Business Media LLC
Date: 05-2012
DOI: 10.2165/11598930-000000000-00000
Abstract: A variety of body size covariates have been used in population pharmacokinetic analyses to describe variability in drug clearance (CL), such as total body weight (TBW), body surface area (BSA), lean body weight (LBW) and allometric TBW. There is controversy, however, as to which body size covariate is most suitable for describing CL across the whole population. Given the increasing worldwide prevalence of obesity, it is essential to identify the best size descriptor so that dosing regimens can be developed that are suitable for patients of any size. The aim of this study was to explore the use of body size covariates in population pharmacokinetic analyses for describing CL. In particular, we sought to determine if any body size covariate was preferential to describe CL and quantify its relationship with CL, and also identify study design features that result in the identification of a nonlinear relationship between TBW and CL. Population pharmacokinetic articles were identified from MEDLINE using defined keywords. A database was developed to collect information about study designs, model building and covariate analysis strategies, and final reported models for CL. The success of inclusion for a variety of covariates was determined. A meta-analysis of studies was then performed to determine the average relationship reported between CL and TBW. For each study, CL was calculated across the range of TBW for the study population and normalized to allow comparison between studies. BSA, LBW, and allometric TBW and LBW relationships with exponents of 3/4, 2/3, and estimated values were evaluated to determine the relationship that best described the data overall. Additionally, joint distributions of TBW were compared between studies reporting a 'nonlinear' relationship between CL and TBW (i.e. LBW, BSA and allometric TBW-shaped relationships) and those reporting 'other' relationships (e.g. linear increase in CL with TBW, ideal body weight or height). A total of 458 out of 2384 articles were included in the analysis, from which 484 pharmacokinetic studies were reviewed. Fifty-six percent of all models for CL included body size as a covariate, with 52% of models including a nonlinear relationship between CL and TBW. No single size descriptor was more successful than others for describing CL. LBW with a fixed exponent of 2/3, i.e. (LBW/50.45)(2/3), or estimated exponent of 0.646, i.e. ∼2/3, was found to best describe the average reported relationship between CL and TBW. The success of identifying a nonlinear increase in CL with TBW was found to be higher for those studies that included a wider range of subject TBW. To the best of our knowledge, this is the first study to have performed a meta-analysis of covariate relationships between CL and body size. Although many studies reported a linear relationship between CL and TBW, the average relationship was found to be nonlinear. LBW with an allometric exponent of ∼2/3 may be most suitable for describing an increase in CL with body size as it accounts for both body composition and allometric scaling principles concerning differences in metabolic rates across size.
Publisher: American Association for Cancer Research (AACR)
Date: 14-05-2018
DOI: 10.1158/1078-0432.CCR-18-0172
Abstract: Purpose: The purpose of this study is to investigate the potential interplay between opioid analgesia and tumor metastasis through modulation of μ-opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential. Experimental Design: Plasma s les were collected from 60 patients undergoing elective lower limb joint replacement preoperatively and at 3, 6, and 24 hours after surgery pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma s les were also collected from 10 healthy volunteers. Alphascreen cyclic AMP assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue hTLR4 were utilized to measure TLR4 activation. Circulating matrix metalloprotease and tissue inhibitor of matrix protease activities were assessed by gelatin zymography and reverse zymography, respectively. Results: Postoperative plasma s les displayed the ability to activate MOR and to inhibit lipopolysaccharide (LPS)-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative s les also displayed altered circulating matrix-degrading enzymes activity potential, but this was correlated neither to opioid administration nor to MOR activation potential. Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point. Clin Cancer Res 24(10) 2319–27. ©2018 AACR.
Publisher: Frontiers Media SA
Date: 07-02-2023
Abstract: Everolimus (EVE) has been used as a calcineurin inhibitor (CNI) minimization/ elimination agent or to augment immunosuppression in lung transplant recipients (LTR) with CNI-induced nephrotoxicity or neurotoxicity. The long-term evidence for survival and progression to chronic lung allograft dysfunction (CLAD) is lacking. The primary aim was to compare survival outcomes of LTR starting EVE-based immunosuppression with those remaining on CNI-based regimens. The secondary outcomes being time to CLAD, incidence of CLAD and the emergence of obstructive (BOS) or restrictive (RAS) phenotypes. Single center retrospective study of 91 LTR starting EVE-based immunosuppression matched 1:1 with LTR remaining on CNI-based immunosuppression. On multivariate analysis, compared to those remaining on CNI-based immunosuppression, starting EVE was not associated with poorer survival [HR 1.04, 95% CI: 0.67–1.61, p = 0.853], or a statistically significant faster time to CLAD [HR 1.34, 95% CI: 0.87–2.04, p = 0.182]. There was no difference in the emergence of CLAD (EVE, [ n = 57, 62.6%] vs. CNI-based [ n = 52, 57.1%], p = 0.41), or the incidence of BOS ( p = 0.60) or RAS ( p = 0.16) between the two groups. Introduction of EVE-based immunosuppression does not increase the risk of death or accelerate the progression to CLAD compared to CNI-based immunosuppression.
Publisher: Oxford University Press (OUP)
Date: 20-01-2015
DOI: 10.1093/JAC/DKU564
Abstract: The objective of this study was to describe the population pharmacokinetics of cefazolin in plasma and the interstitial fluid of subcutaneous tissue of post-trauma critically ill patients and provide clinically relevant dosing recommendations that result in optimal concentrations at the target site. This was a pharmacokinetic study in a tertiary referral ICU. We recruited 30 post-trauma critically ill adult patients and collected serial total and unbound plasma cefazolin concentrations. Interstitial fluid concentrations were determined using in vivo microdialysis. Population pharmacokinetic analysis and Monte Carlo simulations were undertaken with Pmetrics®. Fractional target attainment against an MIC distribution for Staphylococcus aureus isolates was calculated. The mean (SD) age, weight, APACHE II score and CLCR were 37.0 (14.1) years, 86.8 (22.7) kg, 16.9 (5.3) and 163 (44) mL/min, respectively. A three-compartment linear population pharmacokinetic model was most appropriate. Covariates included in the model were CLCR on drug clearance and serum albumin concentration and body weight on the volume of the central compartment. The fractional target attainment for a 1 g intravenous 8-hourly dose for a CLCR of 50 mL/min was 88%, whereas for a patient with a CLCR of 215 mL/min, a dose of 2 g 6-hourly achieved 84% fractional target attainment. Clinicians should be mindful of the effects of elevated CLCR and serum albumin concentrations on dosing requirements for post-trauma critically ill patients.
Publisher: BMJ
Date: 04-2017
Publisher: Wiley
Date: 27-05-2012
DOI: 10.1111/J.1463-1326.2012.01617.X
Abstract: Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open-label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22 creatinine clearances 15-40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250-2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3-5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.
Publisher: American Society for Microbiology
Date: 24-01-2023
DOI: 10.1128/AAC.01312-22
Abstract: In the present study, population pharmacokinetic (PK) analysis was performed based on meropenem data from a prospective study conducted in 114 critically ill patients with a wide range of renal functions and various disease conditions. The final model was a one-compartment model with linear elimination, with creatinine clearance and continuous renal replacement therapy affecting clearance, and total bodyweight impacting the volume of distribution.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.SAPHARM.2019.04.048
Abstract: The rational use of medicines to achieve better patient outcomes is a global concern. This need has pressured the practice of pharmacy to move away from focusing only on dispensing of the drug product towards the patient's appropriate utilization of the medicine. PharmAlliance, a unique partnership among three leading schools of pharmacy at the University of North Carolina at Chapel Hill (United States), Monash University (Australia), and University College London (United Kingdom), convened a Global Summit of Pharmacy Practice Innovation in November 2017 to bring together the leaders of the professional associations of the three countries to dialogue about how to lead the identified changes. A framework of "One Pharmacy Community" resulted from the discussions and was conceptualized from the overarching theme of the Summit. Recognizing and articulating these similarities into a One Pharmacy Community framework enables the development of a consistent global nomenclature of pharmacy services. The four pillars that resulted from the conversation are education, research, practice, and collaboration. Each of these are essential and dependent on the other in order to enable pharmacy practice to meet the global requirements of patient-focused health care design and delivery. This article describes the framework and each of the pillars.
Publisher: Elsevier BV
Date: 2021
DOI: 10.2139/SSRN.3798543
Publisher: MDPI AG
Date: 21-09-2022
DOI: 10.20944/PREPRINTS202209.0323.V1
Abstract: Although various vaccines are now commercially available, they have not been able to stop the spread of COVID-19 infection completely. An excellent strategy to quickly get safe, effective, and affordable COVID-19 treatment is to repurpose drugs that are already approved for other diseases as adjuvants along with the ongoing vaccine regime. The process of developing an accurate and standardized drug repurposing dataset requires a considerable level of resources and expertise due to the commercial availability of an extensive array of drugs that could be potentially used to address the SARS-CoV-2 infection. To address this bottleneck, we created the CoviRx platform. CoviRx is a user-friendly interface that provides access to the data, which is manually curated for COVID-19 drug repurposing data. Through CoviRx, the data curated has been made open-source to help advance drug repurposing research. CoviRx also encourages users to submit their findings after thoroughly validating the data, followed by merging it by enforcing uniformity and integ-rity-preserving constraints. This article discusses the various features of CoviRx and its design principles. CoviRx has been designed so that its functionality is independent of the data it dis-plays. Thus, in the future, this platform can be extended to include any other disease X beyond COVID-19. CoviRx can be accessed at www.covirx.org.
Publisher: Wiley
Date: 23-03-2015
DOI: 10.1111/BCP.12526
Publisher: Wiley
Date: 23-03-2015
DOI: 10.1111/BCP.12525
Publisher: Oxford University Press (OUP)
Date: 18-04-2023
DOI: 10.1093/JAC/DKAD106
Abstract: We aimed to identify rational empirical dosing strategies for cefepime treatment in critically ill patients by utilizing population pharmacokinetics and target attainment analysis. A prospective and opportunistic pharmacokinetic (PK) study was conducted in 130 critically ill patients in two ICU sites. The plasma concentrations of cefepime were determined using a validated LC-MS/MS method. All cefepime PK data were analysed simultaneously using the non-linear mixed-effects modelling approach. Monte Carlo simulations were performed to evaluate the PTA of cefepime at different MIC values following different dose regimens in subjects with different renal functions. The PK of cefepime in critically ill patients was best characterized by a two-compartment model with zero-order input and first-order elimination. Creatinine clearance and body weight were identified to be significant covariates. Our simulation results showed that prolonged 3 h infusion does not provide significant improvement on target attainment compared with the traditional intermittent 0.5 h infusion. In contrast, for a given daily dose continuous infusion provided much higher breakpoint coverage than either 0.5 h or 3 h intermittent infusions. To balance the target attainment and potential neurotoxicity, cefepime 3 g/day continuous infusion appears to be a better dosing regimen than 6 g/day continuous infusion. Continuous infusion may represent a promising strategy for cefepime treatment in critically ill patients. With the availability of institution- and/or unit-specific cefepime susceptibility patterns as well as in idual patients’ renal function, our PTA results may represent useful references for physicians to make dosing decisions.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.SAPHARM.2016.08.005
Abstract: Pharmacist-led medication review is a collaborative service which aims to identify and resolve medication-related problems. To critically evaluate published systematic reviews relevant to pharmacist-led medication reviews in community settings. MEDLINE, EMBASE, International Pharmaceutical Abstracts (IPA), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Cochrane Database of Systematic Reviews (CDSR) were searched from 1995 to December 2015. Systematic reviews of all study designs and outcomes were considered. Methodological quality was assessed using the 11-item Assessment of Multiple Systematic Reviews (AMSTAR) tool. Systematic reviews of moderate or high quality (AMSTAR ≥ 4) were included in the data synthesis. Data extraction and quality assessment was performed independently by two investigators. Of the 35 relevant systematic reviews identified, 24 were of moderate and seven of high quality and were included in the data synthesis. The largest overall numbers of unique primary research studies with favorable outcomes were for diabetes control (78% of studies reporting the outcome), blood pressure control (74%), cholesterol (63%), medication adherence (56%) and medication management (47%). Significant reductions in medication and/or healthcare costs were reported in 35% of primary research studies. Meta-analysis was performed in 12 systematic reviews. Results from the meta-analyses suggested positive impacts on glycosylated hemoglobin, blood pressure, cholesterol, and number and appropriateness of medications. Conflicting findings were reported in relation to hospitalization. No meta-analyses reported reduced mortality. Moderate and high quality systematic reviews support the value of pharmacist-led medication review for a range of clinical outcomes. Further research including more rigorous cost analyses are required to determine the impact of pharmacist-led medication reviews on humanistic and economic outcomes. Future systematic reviews should consider the inclusion of both qualitative and quantitative studies to comprehensively evaluate medication review.
Publisher: Bentham Science Publishers Ltd.
Date: 12-2011
DOI: 10.2174/138920111798808400
Abstract: Pathophysiological changes are common in critically ill patients, and can alter the time course of drug concentrations following dosing. The latter is termed pharmacokinetics (PK), and describes the relationship between dose administered and drug concentrations in plasma. Thus, modifications in PK necessitate dose adjustment, to optimize drug therapy in critical care. An understanding of basic PK principles is therefore required, to improve dosage guidelines in the population treated. Here, we define the key PK parameters, with specific application to critically ill patients. We then overview the methods used for PK analysis, in both research and in the clinical setting. Traditionally, non-compartmental and standard two-stage approaches have been used in small groups of patients with similar demographics and pathophysiology. However, these methods require intensive s ling, and do not explicitly describe inter-in idual variability, or errors associated with measurement or s ling. Population PK (POPPK) modelling is advantageous in this regard, and can use both sparse and rich datasets to provide accurate estimates for between-subject variability (BSV). In addition, POPPK can explore patient parameter-covariate relationships, to account for some of the BSV in PK. This information is useful with assisting in idualized dosing in the clinic. While the above methods are suitable for research, they are too time-consuming in the clinical setting, and Bayesian approaches have been adopted to optimize dosing. These methods, together with POPPK and appropriate study design are recommended for improved dosing in critical care.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2017
DOI: 10.1007/S00228-017-2251-1
Abstract: The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CL Plasma and urine s les were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CL The data (66 patients, 327 observations) were best described by a two-compartment model, and CL The proposed dosing algorithm can be used to dose metformin in patients with various degrees of kidney function to maintain consistent drug exposure. However, there is still marked IIV and therapeutic drug monitoring of metformin plasma concentrations is recommended.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2009
Publisher: CMA Impact Inc.
Date: 12-05-2023
DOI: 10.1503/JPN.230022-L
Publisher: Wiley
Date: 31-08-2023
DOI: 10.1111/BCP.15860
Abstract: To compare pharmacokinetics (PK) and safety of heat‐stable inhaled (IH) oxytocin with intramuscular (IM) oxytocin in women in third stage of labour (TSL), the primary endpoint being PK profiles of oxytocin IH and secondary endpoint of safety. A phase 1, randomised, cross‐over study was undertaken in two UK and one Australian Centre. Subjects were recruited into two groups: Group 1, women in TSL Group 2, non‐pregnant women of childbearing potential (Cohort A, combined oral contraception Cohort B, non‐hormonal contraceptiion). Participants were randomised 1:1 to: Group 1, oxytocin 10 IU (17 μg) IM or oxytocin 240 IU (400 μg) IH immediately after delivery Group 2, oxytocin 5 IU (8.5 μg) intravenously and oxytocin 240 IU (400 μg) IH at two separate dosing sessions. Participants were recruited between 23 November 2016 to 4 March 2019. In Group 1, 17 participants were randomised received either IH ( n = 9) or IM ( n = 8) oxytocin. After IH and IM administration, most plasma oxytocin concentrations were below quantification limits (2 pg/mL). In Group 2 ( n = 14), oxytocin IH concentrations remained quantifiable ≤ 3 hours post‐dose. Adverse events were reported in both groups, with no deaths reported: Group 1, IH n = 3 (33%) and IM n = 2 (25%) Group 2, n = 14 (100%).. Safety profiles of oxytocin IH and IM were similar. However, PK profiles could not be established for oxytocin IH or IM in women in TSL, despite using a highly sensitive and specific assay. NCT02999100. Inhaled and intramuscular oxytocin had similar safety profiles in third stage of labour women (phase 1 study)
Publisher: Springer Science and Business Media LLC
Date: 09-05-2015
Publisher: Elsevier BV
Date: 2021
Publisher: Wiley
Date: 02-2018
DOI: 10.1002/JPPR.1331
Publisher: Springer Science and Business Media LLC
Date: 03-2022
DOI: 10.1007/S40272-022-00493-3
Abstract: Moxifloxacin is a fluoroquinolone that is commonly used in adults, but not children. Certain clinical situations compel pediatric clinicians to use moxifloxacin, despite its potential for toxicity and limited pharmacokinetics (PK) data. Our objective was to further characterize the pharmacokinetics of moxifloxacin in children. We performed an opportunistic, open-label population PK study of moxifloxacin in children 40 kg. The population mean clearance and mean volume of distribution were 18.2 L/h and 167 L, respectively. The oral absorption was described by a first-order process. The estimated extent of oral bioavailability was highly variable (range 20-91%). Total body weight was identified as a covariate on clearance and volume of distribution, and substantially reduced the random unexplained inter-in idual variability for both parameters. No participants experienced suspected serious adverse reactions related to moxifloxacin. These data add to the existing literature to support use of moxifloxacin in children in certain situations however, further prospective studies on the safety and efficacy of moxifloxacin are needed.
Publisher: Wiley
Date: 24-08-2023
DOI: 10.1111/BCP.15865
Abstract: To examine the role of ex vivo oxytocin metabolism in post‐dose peptide measurements. The stability of oxytocin (Study 1) and oxytocinase activity (Study 2) in late‐stage pregnancy blood was quantified using liquid‐chromatography tandem mass‐spectrometry (LC–MS/MS) and a fluorogenic assay, respectively. Analyses were conducted using blood from pregnant women ( weeks gestation) evaluated in lithium heparin (LH), ethylenediaminetetraacetic acid (EDTA) and BD P100 blood collection tubes with or without protease inhibitors. In addition, plasma oxytocin concentrations following administration of oxytocin 240 IU inhaled, 5 IU intravenous or 10 IU intramuscular in women in third stage of labour (TSL) were analysed using enzyme‐linked immunosorbent assay (ELISA) and LC–MS/MS to understand how quantified peptide concentrations differ between these analytical methods (Study 3). Study 1: Oxytocin was stable in blood collected into EDTA tubes with or without protease inhibitors but not in LH tubes. Study 2: Blood collected into all EDTA‐containing collection tubes led to near‐complete inhibition of oxytocinase (≤100 min). In plasma, a 35% reduction in oxytocinase activity was observed in LH tubes with EDTA added. In plasma from late‐stage pregnancy compared to nonpregnant participants, the oxytocinase activity was approximately 11‐fold higher. Study 3: Plasma oxytocin concentrations from nonpregnant or women in TSL following exogenous oxytocin administration were ≤33 times higher when analysed using ELISA vs . LC–MS/MS methods. Collection of blood from late‐stage pregnant women into tubes containing EDTA inhibits oxytocinase effectively stabilizing oxytocin, suggesting low concentrations of oxytocin after dose administration reflect rapid in vivo metabolism.
Publisher: Public Library of Science (PLoS)
Date: 24-04-2015
Publisher: Elsevier BV
Date: 06-2023
Publisher: MDPI AG
Date: 20-09-2022
DOI: 10.20944/PREPRINTS202209.0288.V1
Abstract: The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given the approximately 8,000 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially-available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies compared to in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus have virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be considered.
Publisher: Wiley
Date: 19-06-2020
DOI: 10.1111/BCP.14416
Publisher: American Society for Microbiology
Date: 02-2013
DOI: 10.1128/AAC.01876-12
Abstract: Days to positivity in automated liquid mycobacterial culture have been shown to correlate with mycobacterial load and have been proposed as a useful biomarker for treatment responses in tuberculosis. However, there is currently no quantitative method or model to analyze the change in days to positivity with time on treatment. The objectives of this study were to describe the decline in numbers of mycobacteria in sputum collected once weekly for 8 weeks from patients on treatment for tuberculosis using days to positivity in liquid culture. One hundred forty-four patients with smear-positive pulmonary tuberculosis were recruited from a tuberculosis clinic in Cape Town, South Africa. A nonlinear mixed-effects repeated-time-to-event modeling approach was used to analyze the time-to-positivity data. A biexponential model described the decline in the estimated number of bacteria in patients' sputum s les, while a logistic model with a lag time described the growth of the bacteria in liquid culture. At baseline, the estimated number of rapidly killed bacteria is typically 41 times higher than that of those that are killed slowly. The time to kill half of the rapidly killed bacteria was about 1.8 days, while it was 39 days for slowly killed bacteria. Patients with lung cavitation had higher bacterial loads than patients without lung cavitation. The model successfully described the increase in days to positivity as treatment progressed, differentiating between bacteria that are killed rapidly and those that are killed slowly. Our model can be used to analyze similar data from studies testing new drug regimens.
Publisher: American Society for Microbiology
Date: 12-2011
DOI: 10.1128/AAC.00424-11
Abstract: Fluconazole is a widely used antifungal agent that is extensively reabsorbed in patients with normal renal function. However, its reabsorption can be compromised in patients with acute kidney injury, thereby leading to altered fluconazole clearance and total systemic exposure. Here, we explore the pharmacokinetics of fluconazole in 10 critically ill anuric patients receiving continuous venovenous hemodiafiltration (CVVHDF). We performed Monte Carlo simulations to optimize dosing to appropriate pharmacodynamic endpoints for this population. Pharmacokinetic profiles of initial and steady-state doses of 200 mg intravenous fluconazole twice daily were obtained from plasma and CVVHDF effluent. Nonlinear mixed-effects modeling (NONMEM) was used for data analysis and to perform Monte Carlo simulations. For each dosing regimen, the free drug area under the concentration-time curve (fAUC)/MIC ratio was calculated. The percentage of patients achieving an AUC/MIC ratio greater than 25 was then compared for a range of MIC values. A two-compartment model adequately described the disposition of fluconazole in plasma. The estimate for total fluconazole clearance was 2.67 liters/h and was notably 2.3 times faster than previously reported in healthy volunteers. Of this, fluconazole clearance by the CVVHDF route (CL CVVHDF ) represented 62% of its total systemic clearance. Furthermore, the predicted efficiency of CL CVVHDF decreased to 36.8% when filters were in use h. Monte Carlo simulations demonstrated that a dose of 400 mg twice daily maximizes empirical treatment against fungal organisms with MIC up to 16 mg/liter. This is the first study we are aware of that uses Monte Carlo simulations to inform dosing requirements in patients where tubular reabsorption of fluconazole is probably nonexistent.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.IJANTIMICAG.2011.08.017
Abstract: Vancomycin is currently recommended as first-line therapy for many meticillin-resistant Staphylococcus aureus (MRSA) infections. Recent guidelines have advocated loading doses (25-30 mg/kg) in critically ill patients in order to achieve therapeutic concentrations rapidly. However, weight-based loading doses are still not widely practised. A drug use evaluation was performed to improve the appropriateness of vancomycin initial doses in a population of critically ill adults. An educational intervention incorporating a vancomycin dosing protocol was carried out. Data were collected pre and post intervention. Vancomycin exposure [area under the concentration-time curve (AUC)] in the first 24h was determined using serum concentrations and the Bayesian software TCIWorks. Initial vancomycin doses and exposures were compared between the pre- and post-intervention groups using χ(2) and Mann-Whitney tests. A total of 111 vancomycin courses were analysed in the pre-intervention (n=80) and post-intervention (n=31) groups. Patients in the post-intervention group had significantly higher median weight-based initial doses (20.0mg/kg vs. 12.5mg/kg P<0.001) compared with the pre-intervention group. This corresponded to significantly higher median vancomycin exposures (366.0 mg h/L vs. 262.5 mg h/L P<0.01) in the post-intervention group. Despite higher weight-based initial doses, only 32.3% of patients in the post-intervention group had achieved optimal vancomycin exposures (AUC/minimum inhibitory concentration ratio ≥400) in the first 24h of therapy. A vancomycin dosing protocol improved the initial dosing of vancomycin and the proportion of patients who rapidly achieved optimal vancomycin exposures. However, subtherapeutic exposures were still prevalent and may warrant more vigilant promotion of the dosing protocol to ensure that recommended vancomycin doses are used in this population.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2015
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0735-1097(02)02170-8
Abstract: The goal of this study was to determine the bioactivity of urocortin (Ucn) in experimental heart failure (HF). Urocortin may participate in cardiovascular function and pressure/volume homeostasis. Its effects in HF are unknown. Eight normal sheep and eight sheep with pacing-induced HF received ovine Ucn (10, 50, and 100 mg intravenous boluses at 2-h intervals) in vehicle-controlled studies. Urocortin boluses dose-dependently increased plasma Ucn (p < 0.001). Pharmacokinetics were similar in normal and HF sheep with half-lives approximating 1.3 and 19.5 h for the first and second phases, respectively. In HF, cardiac output increased (twofold), while peripheral resistance, left atrial pressure (both 50% falls: p < 0.001), and mean arterial pressure (p < 0.05) fell. In normal sheep, changes in peripheral resistance and atrial pressure were blunted and in arterial pressure were directionally opposite. Urocortin induced persistent, dose-dependent falls (30% to 50%) in plasma vasopressin, renin activity, aldosterone, natriuretic peptides (all p < 0.001), and endothelin-1 (p < 0.05) in HF sheep, while adrenocorticotrophic hormone and cortisol levels rose acutely (both p < 0.001). In comparison, Ucn in normal sheep resulted in a similar rise in cortisol and fall in aldosterone, no significant effects on plasma renin activity and natriuretic peptides, and a rise in vasopressin. Urocortin produced dose-dependent, sustained increases in urine volume (twofold, p 9-fold rise, p < 0.001), and creatinine clearance (p < 0.001) in HF sheep. No significant renal effects were observed in normal sheep. Urocortin has profound and sustained hemodynamic, hormonal, and renal effects in experimental HF. Urocortin may have a role in pressure/volume homeostasis in HF and may provide a novel therapeutic approach to this disease.
Publisher: MDPI AG
Date: 31-10-2022
DOI: 10.3390/V14112417
Abstract: The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given circa 7817 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies than in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both SARS-CoV-2 Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus, has virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be considered.
Publisher: Springer Science and Business Media LLC
Date: 04-07-2011
DOI: 10.1007/S12603-011-0100-Y
Abstract: Lean body weight (LBW) decreases with age while total body fat increases, resulting in altered drug pharmacokinetics. A semi-mechanistic equation estimating LBW using height, weight and sex has been developed for potential use across a wide range of body compositions. The aim of this study was to determine the ability of the LBW equation to estimate dual energy x-ray absorptiometry-derived fat free mass (FFM(DXA)) in a population of older women with recent hip fracture. Baseline, four and 12 month data obtained from 23 women enrolled in the Sarcopenia and Hip Fracture study were pooled to give 58 measurements. LBW was estimated using the equation: LBW (kg) = (9270 x Wt) / (8780 + (244 x BMI)). Body composition was classified as: 'normal' (BMI 25kg/m(2) and not sarcopenic), 'sarcopenic' (sarcopenic and BMI 25kg/m(2)). The ability of the LBW equation to predict FFMDXA was determined graphically using Bland-Altman plots and quantitatively using the method of Sheiner and Beal. The mean ± SD age of female participants women was 83±7 years (n=23). Sarcopenia was frequently observed (65.2%). Bland-Altman plots demonstrated an underestimation by the LBW equation compared to FFMDXA. The bias (95% CI) and precision (95% CI) calculated using the method of Sheiner and Beal was 0.5kg (-0.7, 1.66kg) and 4.4kg (-3.7, 12.4kg) respectively for pooled data. This equation can be used to easily calculate LBW. When compared to FFMDXA, the LBW equation resulted in a small underestimation on average in this population of women with recent hip fracture. The degree of bias may not be clinically important although further studies of larger heterogeneous cohorts are needed to investigate and potentially improve the accuracy of this predictive equation in larger clinical cohorts.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.SAPHARM.2016.06.003
Abstract: Polypharmacy is highly prevalent in residential aged care facilities (RACFs). Although polypharmacy is sometimes unavoidable, polypharmacy has been associated with increased morbidity and mortality. To identify and prioritize a range of potential interventions to manage polypharmacy in RACFs from the perspectives of health care professionals, health policy and consumer representatives. Two nominal group technique (NGT) sessions were convened in August 2015. A purposive s le (n = 19) of clinicians, researchers, managers and representatives of consumer, professional and health policy organizations were asked to nominate interventions to address the prevalence and appropriateness of medication use. Participants were then asked to prioritize five interventions suitable for possible implementation at the system level. Six of 16 potential interventions were prioritized highest for possible implementation in clinical practice, with two interventions prioritized as second highest. The top interventions in rank order were 'implementation of a pharmacist-led medication reconciliation service for new residents,' 'conduct facility-level audits and feedback to staff and health care professionals,' 'develop deprescribing scripts to assist clinician-resident discussion,' 'develop or revise prescribing guidelines specific to older people with multimorbidity in RACFs,' 'implement electronic medication charts and records' and 'better support Medication Advisory Committees (MACs) to address medication appropriateness.' This study prioritized a range of potential interventions that may be used to assist clinicians and policy makers develop a comprehensive strategy to manage polypharmacy in RACFs.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2015
DOI: 10.1007/S00228-015-1836-9
Abstract: Due to potential drug-drug interactions and subsequent bleeding risk, analgesic use should be reviewed when an oral anticoagulant is initiated. The aim of this study was to compare use of non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesics before and after oral anticoagulant initiation. All in iduals who initiated warfarin, dabigatran, or rivaroxaban between January 2012 and September 2013 were identified from the Finnish Prescription Register. Prevalence of analgesic use during 3 months after oral anticoagulant initiation was compared to analgesic use during 4 months before initiation. Analgesics included were NSAIDs, paracetamol, paracetamol in doses ≥ 2 g/day, tramadol, and other opioids. Conditional logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). In total, 54,025 initiated warfarin, 16,894 rivaroxaban, and 1569 dabigatran. The odds of NSAID use decreased among warfarin initiators (odds ratio (OR) 0.10 95% confidence interval (CI) 0.09-0.10) 2.6% used NSAID after initiation. In contrast, the odds of NSAID use increased among rivaroxaban (OR 3.56 95% CI 3.37-3.75) and dabigatran initiators (OR 1.44 95% CI 1.16-1.78). The proportions using NSAIDs after the initiation were 69 and 32%, respectively. However, NSAID use decreased among dabigatran initiators with confirmed atrial fibrillation (OR 0.46 95% CI 0.23-0.92) and among rivaroxaban initiators with a daily dose of ≥ 15 mg (OR 0.28 95% CI 0.19-0.40). The use of NSAIDs decreases extensively among warfarin initiators which is encouraging. However, the use of NSAIDs increases among rivaroxaban and dabigatran initiators. This is a concern as the bleeding risk may increase due to potential pharmacodynamic interactions.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.SAPHARM.2015.06.007
Abstract: Clinical medication review (CMR) is a structured and collaborative service aimed at identifying and resolving medication-related problems (MRPs). This is the first systematic review of CMR research in Australia. To systematically review the processes and outcomes of CMR in community-settings in Australia. MEDLINE, EMBASE, International Pharmaceutical Abstracts (IPA), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library and the grey literature were searched from 2000 to February 2015. All study designs were considered. Data extraction and quality assessment were performed independently by two investigators. Nine controlled studies, 34 observational and uncontrolled studies, 11 qualitative studies (focus groups and interviews) and nine survey studies were included. The CMRs resulted in identification of MRPs (n = 15 studies, mean 3.6 MPRs per CMR) and improved adherence (n = 3). Reductions in numbers of medications prescribed (n = 3 studies), hospitalizations (n = 3), potentially inappropriate prescribing (n = 3) and costs (n = 6) were demonstrated. Comparisons to a control group, predominately non-recipients of CMR, were made in eleven of 43 studies. Evidence supports additional models that promote interprofessional collaboration and timely referral following hospital discharge. Qualitative research identified low awareness of CMR among eligible non-recipients, while benefits were perceived to outweigh barriers to implementation. Underserved populations include indigenous and culturally and linguistically erse people, recipients of palliative care, those recently discharged from hospital, people with poor medication adherence, those in rural and remote areas, older males, and younger people with long-term, persistent or serious health problems. The available evidence suggests CMR is beneficial in improving the quality use of medications and health outcomes. However, lack of comparator groups in many observational studies limited the strength of conclusions in relation to the impact on clinical outcomes. Addressing access gaps for underserved populations, implementing additional referral pathways, and facilitating greater collaboration between the health professionals represent opportunities for further improvement.
Publisher: Wiley
Date: 06-1999
DOI: 10.1046/J.1365-2125.1999.00938.X
Abstract: 1. To determine the population pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. 2. To see if current starting doses for once daily aminoglycoside dosing are appropriate. 3. To test whether calculating creatinine clearance using an adjusted Cockcroft and Gault method (CLCr,adjusted ) was a better predictor of gentamicin clearance than the standard Cockcroft and Gault method (CLCr,unadjusted ). Nine hundred and fifty-seven patients were dose-in idualized for gentamicin using SeBA-GEN, a Bayesian dosing method. This method returns estimates of the values of gentamicin CL and V d from which the 24 h AUC can be estimated. The goal of therapy was to attain an AUC of 70-100 mg l-1 h depending on the severity of the infection. The population was ided into four groups of differing renal function. Linear regression analysis was performed to determine the relationship between V d and various indices of weight, and gentamicin CL and either CLCr,adjusted or CLCr,unadjusted. The mean V d (+/-s. d.) and CL (+/-s.d.) of gentamicin in our total population were 17.4 (+/-4.1) l and 4.0 (+/-1.8) l h-1, respectively. There was a decrease in V d with reducing renal function when comparing patients with normal renal function and patients with poor renal function. The lower of total body weight (TBW) and lean body weight (LBW), termed dosing weight (DWT), was a slightly better predictor of V d (r2=0.28) than either TBW (r2=0.21) or LBW (r2=0.21). CLCr,adjusted (r2=0.80) was a better predictor of gentamicin CL than CLCr, unadjusted (r2=0.57). The mean population values of V d and CL of gentamicin dosed once daily are similar to those described by others in relation to multiple daily dosing. Given that previous methods have been based on population values of V d and CL from multiple daily dosing, the currently recommended starting doses for once daily aminoglycoside dosing would seem appropriate. The V d reduced with decreasing renal function, with a maximum of 23% difference between patients with normal and poor renal function. The Cockcroft and Gault method of calculating creatinine clearance does not appear to perform well at low values of serum creatinine concentration. An adjustment of the Cockcroft and Gault method is proposed to allow for this.
Publisher: Wiley
Date: 23-02-2021
DOI: 10.1111/BCP.14760
Abstract: During a pandemic caused by a novel pathogen (NP), drug repurposing offers the potential of a rapid treatment response via a repurposed drug (RD) while more targeted treatments are developed. Five steps of model‐informed drug repurposing (MIDR) are discussed: (i) utilize RD product label and in vitro NP data to determine initial proof of potential, (ii) optimize potential posology using clinical pharmacokinetics (PK) considering both efficacy and safety, (iii) link events in the viral life cycle to RD PK, (iv) link RD PK to clinical and virologic outcomes, and optimize clinical trial design, and (v) assess RD treatment effects from trials using model‐based meta‐analysis. Activities which fall under these five steps are categorized into three stages: what can be accomplished prior to an NP emergence (preparatory stage), during the NP pandemic (responsive stage) and once the crisis has subsided (retrospective stage). MIDR allows for extraction of a greater amount of information from emerging data and integration of disparate data into actionable insight.
Publisher: Wiley
Date: 10-09-2018
DOI: 10.1002/PSP4.12319
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.RESUSCITATION.2019.09.033
Abstract: The contribution of adverse medication events to clinical deterioration is unknown. This study aimed to determine the frequency and nature of rapid response system (RRS) calls that clinicians perceived were medication-related using RRS quality arm data. Analysis of routine data prospectively collected by clinicians responding to RRS calls in an Australian acute tertiary academic hospital. Between January 2013 and June 2017, 12,221 adult patients triggered the RRS for 25,906 medical emergency team (MET) and 512 code blue calls. Clinicians identified 433 medication-related RRS calls (1.6%) involving 406 patients (3.3%). These included 418 MET calls (1.3 medication-related MET calls per 1000 admissions) and 15 code blue calls (0.045 medication-related code blue calls per 1000 admissions). Medication-related calls occurred earlier in the admission (p = 0.002) and were more common for patients triggering multiple calls during the same admission (p < 0.001), compared to non-medication-related calls. Medication-related calls most commonly were triggered by low blood pressure (38.3%) and involved cardiovascular (43.0%) and nervous system medications (36.0%). Dose-related toxicity (n = 178) was the most frequent adverse medication event contributing to medication-related calls. One in 30 patients triggering a RRS call experienced medication-related clinical deterioration, most often due to dose related toxicity of cardiovascular system medications. The perceived frequency and potential preventability of this medication-related harm suggest further research is required to increase recognition of medication-related RRS calls by responding clinicians and to reduce the incidence.
Publisher: American Society for Microbiology
Date: 09-2009
DOI: 10.1128/AAC.01200-08
Abstract: Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied. We studied the extent, time course, site(s), and mechanism of this interaction. Seventeen healthy volunteers participated in a randomized, two-way crossover study. Subjects received 320 mg gemifloxacin as an oral tablet without and with 4.5 g probenecid ided in eight oral doses. Drug concentrations in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin was used for noncompartmental analysis, compartmental modeling, and statistics, and NONMEM was used for visual predictive checks. Concomitant administration of probenecid increased plasma gemifloxacin concentrations and amounts excreted in urine compared to baseline amounts. Data are average estimates (percent coefficients of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as the most likely mechanism of the interaction. The estimated K m and V max for the saturable part of renal elimination were 9.16 mg/liter (20%) and 113 mg/h (21%), respectively. Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin than for probenecid. Since probenecid reached an ∼200-times-higher area under the molar concentration-time curve from 0 to 24 h than gemifloxacin, probenecid inhibited the active tubular secretion of gemifloxacin. Probenecid also reduced the nonrenal clearance of gemifloxacin from 25.2 (26%) to 21.0 (23%) liters/h. Probenecid inhibited the renal tubular secretion of gemifloxacin, most likely by a competitive mechanism, and slightly decreased nonrenal clearance of gemifloxacin.
Publisher: Wiley
Date: 21-05-2021
DOI: 10.1111/BCP.14887
Abstract: Oral flucloxacillin may be coadministered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic–pharmacodynamic (PK/PD) targets. The aims of this study were to develop a population PK model of free flucloxacillin when administered orally with probenecid, and to identify optimal dosing regimens for this combination. We performed a prospective observational study of adults (45 participants) treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8‐hourly for proven or probable staphylococcal infections. Steady‐state mid‐dose‐interval flucloxacillin measurements (45 concentrations) were combined with existing data from a crossover study of healthy participants receiving flucloxacillin with and without probenecid (11 participants, 363 concentrations). We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, and used Monte Carlo simulation to explore optimal dosing regimens to attain PK/PD targets proposed in the literature (free drug time above minimum inhibitory concentration). Flucloxacillin disposition was best described by a 1‐compartment model with a lag time and first‐order absorption. Free flucloxacillin clearance depended on probenecid, allometrically‐scaled fat free mass (FFM) and estimated glomerular filtration rate (eGFR). Predicted PK/PD target attainment was suboptimal with standard dosing regimens with flucloxacillin alone, but substantially improved in the presence of probenecid. The simulation results reported can be used to identify dose regimens that optimise flucloxacillin exposure according to eGFR and FFM. Patients with higher FFM and eGFR may require the addition of probenecid and 6‐hourly dosing to achieve PK/PD targets. The regimen was well‐tolerated, suggesting a potential for further evaluation in controlled clinical trials to establish efficacy.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.CTRV.2016.09.014
Abstract: Sinusoidal obstruction syndrome, previously known as veno-occlusive disease (VOD/SOS), is a complication in patients undergoing haemopoietic stem cell transplantation (HSCT). Severe VOD/SOS, including progression to multi-organ failure, has resulted in a mortality of greater than 80%. Defibrotide's varying pharmacological actions, particularly on endothelial cells, make it is a useful agent to consider for prophylaxis and treatment of VOD/SOS. Barriers to its routine use include the high acquisition cost and the fact that neither the oral or parenteral formulations are licensed products in many countries at this time. This review summarises available literature on the use of defibrotide in the management of VOD/SOS. Publications consist predominantly of single centre cohort studies and case series. Available evidence indicates that defibrotide is effective in the management of VOD/SOS. Using defibrotide prophylaxis should also be considered, especially in the paediatric setting, where there are available results from a large, open label, randomized controlled trial. Patient outcome data from the larger studies and compassionate programs can inform consensus recommendations on dosing regimen and criteria for the treatment of VOD/SOS with defibrotide in the adult population. The reviewed literature indicates an effective and safe dose for treatment is 25mg/kg/day, continued for at least 14days or until complete response is achieved. Further studies are required to determine the optimal dose and duration of treatment in both paediatric patients and adults. Recent recommendations and a phase 3 trial using historical controls indicate that defibrotide should be included as a pharmacotherapy option in protocols guiding management of VOD/SOS.
Publisher: Wiley
Date: 12-04-2010
Publisher: Wiley
Date: 10-01-2011
Publisher: Wiley
Date: 06-2004
Publisher: American Society for Microbiology
Date: 11-2012
DOI: 10.1128/AAC.00937-12
Abstract: Piperacillin in combination with tazobactam is one of the most commonly used intravenous antibiotics. There is evidence for a possible saturable elimination of piperacillin. Therefore, the saturable elimination and its impact on the choice of optimal dosage regimens were quantified. In a randomized crossover study, 10 healthy volunteers received 1,500 mg and 3,000 mg of piperacillin as 5-min intravenous infusion. Population pharmacokinetics based on plasma and urine data were determined utilizing NONMEM and S-ADAPT. Probabilities of target attainment (PTAs) were compared for different models and dosage regimens, based on the target time of the non-protein-bound concentration above the MIC of at least 50% of the dosing interval. Total clearance of piperacillin was 18% (geometric mean ratio, 90% confidence interval, 11 to 24%) lower ( P 0.01), and renal clearance was 24% (9 to 37%) lower ( P = 0.02) at the high compared to the low dose. The final model included first-order nonrenal elimination and parallel first-order and mixed-order renal elimination. Nonrenal clearance was 5.44 liter/h (coefficient of variation, 18%), first-order renal clearance was 4.42 liter/h (47%), and the maximum elimination rate of mixed-order renal elimination was 219 mg/h (84%), with a Michaelis-Menten constant of 36.1 mg/liter (112%). Compared to models with saturable elimination, a linear model predicted up to 10% lower population PTAs for high-dose short-term infusions (6 g every 8 h) and up to 4% higher population PTAs for low-dose continuous infusions (6 g/day). While renal elimination of piperacillin was saturable at therapeutic concentrations, the extent of saturation of nonrenal clearance was small. The influence of saturable elimination on PTAs for clinically relevant dosage regimens was relatively small.
Publisher: Wiley
Date: 11-09-2008
Publisher: American Society for Microbiology
Date: 05-2017
DOI: 10.1128/AAC.02642-16
Abstract: Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MIC meropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼10 7.5 CFU/ml 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ∼10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log 10 ). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h regrowth then occurred with 0.5- and 1-g regimens with normal renal function ( fT ×MIC = 56 and 69%, fC min /MIC 2) the emergence of less-susceptible populations (≥32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function ( fT ×MIC ≥ 82%, fC min /MIC ≥ 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2020
DOI: 10.1007/S00520-019-05290-2
Abstract: To assess the impact of a pathway allowing nurse initiation of first dose intravenous (IV) antibiotics on time to antibiotic administration (TTA) in adult inpatients with febrile neutropenia (FN). This study evaluated the impact on TTA of a clinical pathway (November 2017 to April 2018) allowing nurse initiation of pre-prescribed antibiotics in adult haematology patients with FN, compared with a prior cohort (November 2016 to April 2017) in which antibiotics were only prescribed and administered after medical review. The primary endpoint for comparison was TTA, calculated as the time between the first recorded fever and IV antibiotic administration. Secondary endpoints included appropriateness of initial antibiotic choice, 30-day all-cause mortality and admission to intensive care unit (ICU). Forty-seven eligible FN episodes in 40 patients and 61 episodes in 52 patients were evaluated in the pre- and post-implementation groups, respectively. Baseline characteristics were comparable between groups. Median (IQR) TTA, in the pre-implementation group [66 min (40-100 min)] was significantly prolonged versus post-implementation group [29 min (20-41 min) p 0.99) between pre- and post-implementation groups, respectively. A pathway allowing nurse initiation of pre-prescribed antibiotic orders for FN significantly reduced TTA from first recorded fever and increased the proportion of appropriate initial antibiotic choices without significantly impacting on patient outcomes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2004
DOI: 10.1097/00007691-200406000-00011
Abstract: The current approach for therapeutic drug monitoring in renal transplant recipients receiving mycophenolate mofetil (MMF) is measurement of total mycophenolic acid (MPA) concentration. Because MPA is highly bound, during hypoalbuminemia the total concentration no longer reflects the free (pharmacologically active) concentration. The authors investigated what degree of hypoalbuminemia causes a significant change in protein binding and thus percentage free MPA. Forty-two renal transplant recipients were recruited for the study. Free and total concentrations of MPA (predose, and 1, 3, and 6 hours post-MMF dose s les) and plasma albumin concentrations were determined on day 5 posttransplantation. Six-hour area under the concentration-time curve (AUC(0-6)) values were calculated for free and total MPA, and percentage free MPA was determined for each patient. The authors found a significant relationship between low albumin concentrations and increased percentage free MPA (Spearman correlation = -0.54, P or = 3%) in this patient population was 31 g/L. At this cutoff value albumin was found to be a good predictor of altered free MPA percentage, with a sensitivity and specificity of 0.75 and 0.80, respectively, and an area under the ROC curve of 0.79. To rationalize MMF dosing regimens in hypoalbuminemic patients (plasma albumin < or = 31 g/L), clinicians should consider monitoring the free MPA concentration.
Publisher: Wiley
Date: 28-10-2008
Publisher: Springer Science and Business Media LLC
Date: 19-05-2022
Publisher: Cambridge University Press (CUP)
Date: 12-2014
DOI: 10.1086/678596
Abstract: Multidrug-resistant bacteria are major causes of nosocomial infections and are associated with considerable morbidity, mortality, and healthcare costs. Preventive strategies have therefore become increasingly important. Mathematical modeling has been widely used to understand the transmission dynamics of nosocomial infections and the quantitative effects of infection control measures. This review will explore the principles of mathematical modeling used in nosocomial infections and discuss the effectiveness of infection control measures investigated using mathematical modeling. Infect Control Hosp Epidemiol 2014 (12):1521–1530
Publisher: Springer Science and Business Media LLC
Date: 11-2007
Abstract: The global epidemic of obesity has led to an increased prevalence of chronic diseases and need for pharmacological intervention. However, little is known about the influence of obesity on the drug exposure profile, resulting in few clear dosing guidelines for the obese. Here we present a semi-mechanistic model for lean body weight (LBW) that we believe is sufficiently robust to quantify the influence of body composition on drug clearance, and is therefore an ideal metric for adjusting chronic dosing in the obese.
Publisher: MDPI AG
Date: 20-09-2022
DOI: 10.20944/PREPRINTS202209.0310.V1
Abstract: SARS-CoV-2, is the cause of the COVID-19 pandemic which has claimed more than six million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA approved molecules with established safety profiles that have a plausible mechanism for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising repurposable drug candidates that are safe, efficacious, and cost-effective for the treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx, www.covirx.org/) that was also developed to enable scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.
Publisher: Wiley
Date: 04-06-2004
Publisher: Springer Science and Business Media LLC
Date: 08-07-2017
DOI: 10.1007/S40262-016-0430-3
Abstract: Lithium is a well-established treatment for bipolar I disorder in adults. However, there is a paucity of information on its pharmacokinetics harmacodynamics in children and adolescents. We aimed to develop the first lithium dosage regimens based on population pharmacokinetics harmacodynamics for paediatric patients. Lithium concentrations, Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I) scores over 24 weeks were available from 61 paediatric patients with bipolar I disorder. The population pharmacokinetics harmacodynamics were co-modelled. Concentrations and clinical effects following several dosage regimens were predicted by Monte Carlo simulations. The pharmacokinetics were well characterised by a two compartment model with linear elimination. Including the effect of total body weight (TBW) or lean body weight (LBW) on clearance and volume of distribution decreased the unexplained inter-in idual variability by up to 12 %. The population mean (inter-in idual variability) clearance was 1.64 L/h/53 kg LBW When accounting for body size, the pharmacokinetic parameters in paediatric patients were within the range of estimates from adults. Pharmacokinetic harmacodynamic modelling supported development of practical scientifically-based dosage regimens for paediatric patients.
Publisher: Springer Science and Business Media LLC
Date: 2004
DOI: 10.2165/00003088-200443150-00007
Abstract: To develop a standard weight descriptor that can be used for estimation of patient size for obese patients. Data were available from 3849 patients: 2839 from oncology patients (index data set) and 1010 from general medical patients (validation data set). The patients had a wide range of age (16-100 years), weight (25-165 kg) and body mass index (BMI) [12-52 kg/m2] in both data sets. From the normal-weight patients in the oncology data set, an equation for male and female patients was developed to predict their normal weight as the sum of the lean body mass and normal fat body mass. The equations were evaluated by predicting the weight of patients in the general medical data set who had a normal BMI (<25 kg/m2). In addition, the clinical utility of the predicted normal weight (PNWT) descriptor was assessed by (i) comparing body surface area and allometric scaling calculations based on actual weight of obese patients versus PNWT and (ii) comparing the predictive performance of creatinine clearance using the Cockcroft and Gault equation when using actual weight of obese patients versus PNWT to predict gentamicin clearance. The PNWT equations developed from the oncology data set predicted accurately the actual weight of normal weighted (BMI 35 kg/m2. The use of PNWT in the Cockcroft and Gault equation provided better predictions of gentamicin clearance than when using actual weight. A standard weight descriptor has been developed that can be used in dosing algorithms for patients who are obese (BMI >30 kg/m2).
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.DRUDIS.2022.103422
Abstract: The use of real-world data in drug repurposing has emerged due to well-established advantages of drug repurposing in supplementing de novo drug discovery and incentives in incorporating real-world evidence in regulatory approvals. We conducted a scoping review to characterize repurposing studies using real-world data and discuss their potential challenges and solutions. A total of 250 studies met the inclusion criteria, of which 36 were original studies on hypothesis generation, 101 on hypothesis validation, and seven on safety assessment. Key challenges that should be addressed for future progress in using real-world data for repurposing include isolated data sources with poor clinical granularity, false-positive signals from data mining, the sensitivity of hypothesis validation to bias and confounding, and the lack of clear regulatory guidance.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.SAPHARM.2016.04.009
Abstract: Pharmacy workforce planning has been relatively static for many decades. However, like all industries, health care is exposed to potentially disruptive technological changes. Automated dispensing systems have been available to pharmacy for over a decade and have been applied to a range of repetitive technical processes which are at risk of error, including record keeping, item selection, labeling and dose packing. To date, most applications of this technology have been at the local level, such as hospital pharmacies or single-site community pharmacies. However, widespread implementation of a more centralized automated dispensing model, such as the 'hub and spoke' model currently being debated in the United Kingdom, could cause a 'technology shock,' delivering industry-wide efficiencies, improving medication accessibility and lowering costs to consumers and funding agencies. Some of pharmacists' historical roles may be made redundant, and new roles may be created, decoupling pharmacists to a certain extent from the dispensing and supply process. It may also create an additional opportunity for pharmacists to be acknowledged and renumerated for professional services that extend beyond the dispensary. Such a change would have significant implications for the organization and funding of community pharmacy services as well as pharmacy workforce planning. This paper discusses the prospect of centralized automated dispensing systems and how this may impact on the pharmacy workforce. It concludes that more work needs to be done in the realm of pharmacy workforce planning to ensure that the introduction of any new technology delivers optimal outcomes to consumers, insurers and the pharmacy workforce.
Publisher: Public Library of Science (PLoS)
Date: 20-11-2020
DOI: 10.1371/JOURNAL.PONE.0241968
Abstract: The non-medical use of prescription stimulants such as methylphenidate, dex hetamine and modafinil is increasing in popularity within tertiary academic settings. There is a paucity of information on awareness, attitudes, and acceptability by professionals of use in this context. This study aimed to investigate professionals’ knowledge of and attitudes towards the use of cognitive enhancers (CEs) in academic settings, and their willingness to use a hypothetical CE. A mail survey was sent to doctors, pharmacists, nurses, accountants and lawyers in New Zealand. These disciplines were chosen as they require professional registration to practice. The questionnaire comprised four sections: (1) demographics, (2) knowledge of CEs, (3) attitudes towards the use of CEs, and (4) willingness to use hypothetical CEs. The response rate was 34.5% (414/1200). Overall, participants strongly disagreed that it was fair to allow university students to use CEs for cognitive enhancement (Mdn = 1, IQR: 1,3), or that it is ethical for students without a prescription to use cognitive enhancers for any reason (Mdn = 1, IQR: 1,2). Professions differed in their attitudes towards whether it is ethical for students without a prescription to use CEs for any reason ( p = 0.001, H 31.527). Divergent views and lack of clear consensus within professions and between professionals on the use of CEs have the potential to influence both professionals and students as future professionals. These ergent views may stem from differences in the core values of self-identity as well as extrinsic factors of acceptability within the profession in balancing the elements of opportunity, fairness and authenticity in cognitive enhancement. Further research is required to inform the development of policy and guidelines that are congruent with all professions.
Publisher: Oxford University Press (OUP)
Date: 19-09-2007
DOI: 10.1093/QJMED/HCM072
Abstract: Although QT prolongation is associated with increased risk of torsade de pointes (TdP), the precise relationship is not well defined. To evaluate the performance of a QT nomogram in assessing the risk of TdP from QT-RR combinations. Systematic review. We systematically searched MEDLINE/EMBASE for cases of drug-induced TdP. Controls were patients taking non-cardiotoxic drugs in overdose. Inclusion criteria were definite TdP, normal ECG before or after the event, association with a drug/toxin and QT-RR measurements available. The upper bound of a QT-RR cloud diagram developed from human preclinical studies was converted into a QT nomogram [QT vs. heart rate (HR)]. QT-HR combinations for TdP cases and controls were plotted with the QT nomogram, and curves corresponding to a QTc = 440 ms and QTc = 500 ms for comparison (Bazett's correction). We identified 129 cases of TdP. TdP cases occurred at lower HR values with longer QT intervals, with most cases occurring at HR 30-90 bpm. Controls were more evenly distributed, with HR 40-160 bpm. The sensitivity and specificity of the QT nomogram were 96.9% (95%CI 93.9-99.9) and 98.7% (95%CI 96.8-100), respectively. For Bazett QTc = 440 ms, sensitivity and specificity were 98.5% (95%CI 96.3-100) and 66.7% (95%CI 58.6-74.7), respectively, whereas for Bazett QTc =500 ms they were 93.8% (95%CI 89.6-98.0) and 97.2% (95%CI 94.3-100), respectively. The QT nomogram is a clinically relevant risk assessment tool that accurately predicts arrhythmogenic risk for drug-induced QT prolongation. Further prospective evaluation of the nomogram is needed.
Publisher: Springer Science and Business Media LLC
Date: 04-2009
DOI: 10.1007/S11095-009-9873-7
Abstract: To develop a predictive pharmacokinetic model for propofol that could inform development of a dosing strategy for the obese population. A prior model that included a nonlinear relationship between clearance (CL) and Total Body Weight (TBW) was re-parameterized with a linear relationship between CL and Lean Body Weight (LBW). The predictive performance of both models was compared and the LBW model used to explore propofol exposure from normal to obese patients. A dosing strategy was evaluated that normalized awakening time across a range of patient weights. The predictive performance of the LBW model was similar to the nonlinear TBW model for normal weighted subjects. Simulations in 70-160 kg subjects indicated that dosing linearly on TBW (label recommendation), in contrast to LBW, resulted in increased plasma concentrations in the larger weight groups. This result might explain why obese subjects take longer to awaken from anesthesia compared to normal weighted subjects. Dosing by LBW normalized patient awakening times across this weight range. LBW as a covariate provides a plausible mechanistic explanation for an observed nonlinear increase in drug CL with TBW and may be suitable for developing dosing strategies that are appropriate for use in the obese population.
Publisher: Frontiers Media SA
Date: 20-01-2023
Abstract: Everolimus (EVE) provides an alternative to maintenance immunosuppression when conventional immunosuppression cannot be tolerated. EVE can be utilized with a calcineurin inhibitor (CNI) minimization or elimination strategy. To date, clinical studies investigating EVE after lung transplant (LTx) have primarily focused on the minimization strategy to preserve renal function. The primary aim was to determine the preferred method of EVE utilization for lung transplant recipients (LTR). To undertake this aim, we compared the safety and efficacy outcomes of EVE as part of minimization and elimination immunosuppressant regimens. Single center retrospective study of 217 LTR initiated on EVE (120 CNI minimization and 97 CNI elimination). Survival outcomes were calculated from the date of EVE commencement. On multivariate analysis, LTR who received EVE as part of the CNI elimination strategy had poorer survival outcomes compared to the CNI minimization strategy [HR 1.61, 95% CI: 1.11–2.32, p =0.010]. Utilization of EVE for renal preservation was associated with improved survival compared to other indications [HR 0.64, 95% CI: 0.42–0.97, p =0.032]. EVE can be successfully utilized for maintenance immunosuppression post LTx, particularly for renal preservation. However, immunosuppressive regimens containing low dose CNI had superior survival outcomes, highlighting the importance of retaining a CNI wherever possible.
Publisher: Oxford University Press (OUP)
Date: 21-10-2014
DOI: 10.1093/JAC/DKU413
Abstract: To describe the interstitial fluid (ISF) and plasma pharmacokinetics of meropenem in patients on continuous venovenous haemodiafiltration (CVVHDF). This was a prospective observational pharmacokinetic study. Meropenem (500 mg) was administered every 8 h. CVVHDF was targeted as a 2-3 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2 and a blood flow rate of 200 mL/min. Serial blood (pre- and post-filter), filtrate/dialysate and ISF concentrations were measured on 2 days of treatment (Profiles A and B). Subcutaneous tissue ISF concentrations were determined using microdialysis. A total of 384 s les were collected. During Profile A, the comparative median (IQR) ISF and plasma peak concentrations were 13.6 (12.0-16.8) and 40.7 (36.6-45.6) mg/L and the trough concentrations were 2.6 (2.4-3.4) and 4.9 (3.5-5.0) mg/L, respectively. During Profile B, the ISF trough concentrations increased by ∼40%. Meropenem ISF penetration was estimated at 63% (60%-69%) and 69% (65%-74%) for Profiles A and B, respectively, using comparative plasma and ISF AUCs. For Profile A, the plasma elimination t1/2 was 3.7 (3.3-4.0) h, the volume of distribution was 0.35 (0.25-0.46) L/kg, the total clearance was 4.1 (4.1-4.8) L/h and the CVVHDF clearance was 2.9 (2.7-3.1) L/h. This is the first known report of concurrent plasma and ISF concentrations of a meropenem antibiotic during CVVHDF. We observed that the ISF concentrations of meropenem were significantly lower than the plasma concentrations, although the present dose was appropriate for infections caused by intermediately susceptible pathogens (MIC≤4 mg/L).
Publisher: American Society for Microbiology
Date: 07-2012
DOI: 10.1128/AAC.00048-12
Abstract: Despite the important role of fluoroquinolones and the predominant use of ofloxacin for treating multidrug-resistant tuberculosis in South Africa, there are limited data on ofloxacin pharmacokinetics in patients with multidrug-resistant tuberculosis, no ofloxacin pharmacokinetic data from South African patients, and no direct assessment of the relationship between ofloxacin pharmacokinetics and the MIC of ofloxacin of patient isolates. Our objectives are to describe ofloxacin pharmacokinetics in South African patients being treated for multidrug-resistant tuberculosis and assess the adequacy of ofloxacin drug exposure with respect to the probability of pharmacodynamic target attainment (area under the time curve/MIC ratio of at least 100). Sixty-five patients with multidrug-resistant tuberculosis were recruited from 2 hospitals in South Africa. We determined the ofloxacin MICs for the Mycobacterium tuberculosis isolates from baseline sputum specimens. Patients received daily doses of 800 mg ofloxacin, in addition to other antitubercular drugs. Patients underwent pharmacokinetic s ling at steady state. NONMEM was used for data analysis. The population pharmacokinetics of ofloxacin in this study has been adequately described. The probability of target attainment expectation in the study population was 0.45. Doubling the dose to 1,600 mg could increase this to only 0.77. The currently recommended ofloxacin dose appeared inadequate for the majority of this study population. Studies to assess the tolerability of higher doses are warranted. Alternatively, ofloxacin should be replaced with more potent fluoroquinolones.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.AUCC.2021.02.008
Abstract: Medical emergency teams use medications to rescue deteriorating patients. Medication management is the system of steps and processes, including prescribing, distribution, administration, and monitoring, to achieve the best outcomes from medication use. Systems or standards for medication management by medical emergency teams have not been defined. The aim of the study was to propose potential solutions to improve medical emergency team medication management by evaluating medication supply and related medication management practices during medical emergency team activations and understanding clinicians' perceptions about medical emergency team medication management in acute hospitals. A prospective multicentre audit of intensive care unit-equipped hospitals in Victoria, Australia, was conducted. After advertisement and invitation via scheduled email newsletters to hospitals, a representative of the medical emergency team from each hospital self-administered an online audit tool during December 2019 and January 2020. Audit data were analysed descriptively, and perceptions were analysed using content analysis. Responses were received from 32 of the 44 (72.7%) eligible hospitals. At 17 of the 32 (53.1%) hospitals, arrest trolleys provided medications for medical emergency team activations, in addition to arrest calls. At 15 of the 32 (46.9%) hospitals, separate, dedicated medical emergency team medication supplies were used to care for deteriorating patients. Dedicated medical emergency team supplies contained a median of 20 (range = 8-37) medications, predominantly cardiovascular (median = 8, mode = 7, range = 4-16) and neurological medications (median and mode = 6, range = 0-11). Variation was observed in all storage and other supply-related medication management practices studied. The four most frequent categories of clinicians' perceptions described systematic challenges with availability of the right medication in the right place at the right time. Current supply and related medication management practices and clinicians' perceptions demonstrated further development is necessary for medication management to meet the needs of medical emergency team clinicians and their patients.
Publisher: Wiley
Date: 21-01-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2012
Publisher: Wiley
Date: 02-08-2021
DOI: 10.1111/BCP.14997
Publisher: Wiley
Date: 24-11-2022
DOI: 10.1002/PSP4.12886
Abstract: Studies that focus on in idual covariates, while ignoring their interactions, may not be adequate for model‐informed precision dosing (MIPD) in any given patient. Genetic variations that influence protein synthesis should be studied in conjunction with environmental covariates, such as cigarette smoking. The aim of this study was to build virtual twins (VTs) of real patients receiving clozapine with interacting covariates related to genetics and environment and to delineate the impact of interacting covariates on predicted clozapine plasma concentrations. Clozapine‐treated patients with schizophrenia ( N = 42) with observed clozapine plasma concentrations, demographic, environmental, and genotype data were used to construct VTs in Simcyp. The effect of increased covariate virtualization was assessed by performing simulations under three conditions: “low” (demographic), “medium” (demographic and environmental interaction), and “high” (demographic and environmental/genotype interaction) covariate virtualization. Increasing covariate virtualization with interaction improved the coefficient of variation ( R 2 ) from 0.07 in the low model to 0.391 and 0.368 in the medium and high models, respectively. Whereas R 2 was similar between the medium and high models, the high covariate virtualization model had improved accuracy, with systematic bias of predicted clozapine plasma concentration improving from −138.48 ng/ml to −74.65 ng/ml. A high level of covariate virtualization (demographic, environmental, and genotype) may be required for MIPD using VTs.
Publisher: Oxford University Press (OUP)
Date: 30-10-2015
DOI: 10.1093/JAC/DKV343
Abstract: The primary objectives were to investigate the prescribing practices of primary antifungal prophylaxis (PAP) and incidence of invasive fungal disease (IFD) in adult patients with ALL receiving induction-consolidation chemotherapy. Secondary objectives were to determine risk factors for IFD and resource utilization associated with IFD. A retrospective chart review of adult patients with ALL from commencement of induction until completion of consolidation chemotherapy was undertaken from January 2008 to June 2013 in four hospitals in Melbourne, Australia. IFD was classified according to the revised European Organisation for Research and Treatment of Cancer criteria. Cost analysis was performed from an Australian public hospital perspective. Ninety-eight patients were included in the audit 83 (85%) received PAP. Most patients (49/83, 59%) switched between two different antifungal agents, predominantly between liposomal hotericin B and an azole. Five proven robable and six possible IFD cases were identified. Proven robable IFD was most common in patients receiving the BFM95 chemotherapy protocol. The incidence of proven robable IFD was significantly lower in patients receiving PAP compared with those who did not (2/78, 2.6% versus 3/14, 21.4% P = 0.024). For every five patients receiving PAP, one proven robable IFD case would be prevented. Proven robable IFD was associated with an additional median cost of 121,520 Australian dollars (95% CI: 90,781-180,141 Australian dollars P < 0.001) compared with patients without IFD. This is the first multicentre study evaluating PAP use in patients with ALL. With the caveats of interpretation of retrospective, non-randomized data, PAP was associated with a reduced IFD risk.
Publisher: AMPCo
Date: 12-02-2021
DOI: 10.5694/MJA2.50942
Publisher: American Society for Microbiology
Date: 05-2018
DOI: 10.1128/AAC.00078-18
Abstract: Augmented renal clearance (ARC) in critically ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against Pseudomonas aeruginosa by use of the hollow-fiber infection model (HFIM). Using a P. aeruginosa isolate from a critically ill patient and static-concentration time-kill experiments (SCTKs), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, against two inocula (10 5.8 and 10 7.6 CFU/ml) over 72 h. We subsequently evaluated the effects of optimized piperacillin (4 g every 4 h [q4h], given as 0.5-h infusions) plus tobramycin (5 mg/kg of body weight q24h, 7 mg/kg q24h, or 10 mg/kg q48h, given as 0.5-h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 ml/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin and against the low inoculum) achieved synergistic killing (≥2 log 10 versus the most active monotherapy at 48 h and 72 h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4-log 10 initial killing followed by regrowth at 24 h and resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log 10 at 13 h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5-log 10 killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin-tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear to be highly promising for effective and early treatment, even in the near-worst-case scenario of ARC.
Publisher: Wiley
Date: 04-07-2007
Publisher: Springer Science and Business Media LLC
Date: 12-08-2011
DOI: 10.1038/GT.2010.113
Abstract: Small interfering RNA (siRNA) shows great promise in cancer therapy, but its effectiveness in vivo still remains a crucial issue for its transition into the clinics. Although the successful use of polyethylene glycol (PEG)ylated lipidic delivery systems have already been reported, most of the formulation procedures used are labour intensive and also result in unstable end products. We have previously developed a simple yet efficient hydration-of-freeze-dried-matrix (HFDM) method to entrap siRNA within lipid particles, in which the products exhibited superior stability. Here, we show that these HFDM-formulated particles are stable in the presence of serum and can deliver siRNA efficiently to tumours after intravenous administration. Using these particles, around 50% knockdown of the target gene expression was observed in tumours. With the use of siRNA targeting the E6/7 oncogenes expressed in cervical cancer, we showed a 50% reduction in tumour size. This level of tumour growth suppression was comparable to that achieved from cisplatin at the clinically used dose. Overall, our results demonstrate the feasibility of using HFDM-formulated particles to systematically administer E6/7-targeted siRNA for cervical cancer treatment. The simplicity of preparation procedure along with superior product stability obtained from our method offers an innovative approach for the in vivo delivery of siRNA.
Publisher: Oxford University Press (OUP)
Date: 26-05-2016
DOI: 10.1093/JAC/DKW153
Abstract: Pathophysiological changes in critically ill patients can cause severely altered pharmacokinetics and widely varying antibiotic exposures. The impact of altered pharmacokinetics on bacterial killing and resistance has not been characterized in the dynamic hollow-fibre in vitro infection model (HFIM). A clinical Pseudomonas aeruginosa isolate (piperacillin MIC 4 mg/L) was studied in the HFIM (inoculum ∼10(7) cfu/mL). Pharmacokinetic profiles of three piperacillin dosing regimens (4 g 8-, 6- and 4-hourly, 30 min intravenous infusion) as observed in critically ill patients with augmented renal clearance (ARC), normal renal function or impaired renal function (creatinine clearances of 250, 110 or 30 mL/min, respectively) were simulated over 7 days. The time courses of total and less-susceptible populations and MICs were determined. Mechanism-based modelling was performed in S-ADAPT. For all regimens with ARC and regimens with 8- or 6-hourly dosing with normal renal function, initial killing of ≤∼2 log10 was followed by regrowth to 10(8)-10(9) cfu/mL at 48 h. For 8- and 6-hourly dosing at normal renal function, the proportion of less-susceptible colonies increased ∼10-100-fold above those in ARC and control arms. Regimens achieving an fCmin of ≥5× MIC resulted in bacterial killing of 3-4 log10 without regrowth and suppressed less-susceptible populations to ≤∼2 log10. The mechanism-based model successfully quantified the time course of bacterial growth, killing and regrowth. Only high piperacillin concentrations prevented regrowth of P. aeruginosa. In idualized dosing regimens that account for altered pharmacokinetics and aim for higher-than-standard antibiotic exposures to achieve an fCmin of ≥5× MIC were required to maximize bacterial killing and suppress emergence of resistance.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.IJANTIMICAG.2018.12.014
Abstract: We have evaluated the literature to review optimal dosing and monitoring of intravenous vancomycin in adults, in response to evolving understanding of targets associated with efficacy and toxicity. The area under the total concentration-time curve (0-24 h) ided by the minimum inhibitory concentration (AUC
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.IJANTIMICAG.2014.01.009
Abstract: This prospective pharmacokinetic study aimed to describe plasma and interstitial fluid (ISF) pharmacokinetics of piperacillin and tazobactam in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF). Piperacillin/tazobactam (4g/0.5g) was administered every 8h and CVVHDF was performed as a 3-3.5L/h exchange using a polyacrylonitrile filter with a surface area of 1.05m(2). Serial blood (pre- and post-filter), filtrate/dialysate, urine and ISF concentrations were measured. Subcutaneous tissue ISF concentrations were determined using microdialysis. A total of 407 s les were collected. Median peak plasma concentrations were 210.5 (interquartile range=161.5-229.0) and 29.4 (27.9-32.0) mg/L and median trough plasma concentrations were 64.3 (49.0-68.9) and 12.3 (7.7-13.7) mg/L for piperacillin and tazobactam, respectively. The plasma elimination half-life was 6.4 (4.6-8.7) and 7.3 (4.6-11.8) h, volume of distribution 0.42 (0.29-0.49) and 0.32 (0.24-0.36) L/kg, total clearance 5.1 (4.2-6.2) and 3.8 (3.3-4.2) L/h and CVVHDF clearance 2.5 (2.3-3.1) and 2.5 (2.3-3.2) L/h for piperacillin and tazobactam, respectively. The tissue penetration ratio or ratio of area under the concentration-time curve of the unbound drug in ISF to plasma (unbound AUCISF/AUCplasma) was ca. 1 for both piperacillin and tazobactam. This is the first report of concurrent plasma and ISF concentrations of piperacillin and tazobactam during CVVHDF. For the CVVHDF settings used in this study, a dose of 4.5g piperacillin/tazobactam administered evry 8h resulted in piperacillin concentrations in plasma and ISF >32mg/L throughout most of the dosing interval.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.TRANSPROCEED.2017.07.013
Abstract: Lung transplantation (LTx) is a successful treatment option for end-stage lung disease, and immunosuppressant regimens, utilized to prevent rejection of the transplanted graft, are paramount to maintaining long-term graft survival. Immunosuppression can be classified as induction, maintenance, and antirejection therapy. This article focuses on maintenance immunosuppression that includes a combination of a calcineurin inhibitor (CNI), cell cycle inhibitor, and corticosteroid. CNIs remain the cornerstone of immunosuppression following LTx, and tacrolimus is now the preferred CNI, based on a better adverse effect profile and some limited evidence for enhanced efficacy. Tacrolimus is associated with a number of unique challenges post-LTx, with erratic and highly variable absorption making it difficult to achieve and maintain therapeutic levels. Current methods of therapeutic drug monitoring are extrapolated from models in liver and kidney transplants and are not validated in the LTx population. Alternative methods of delivering tacrolimus can address some of the issues associated with their use and can be utilized in particular clinical scenarios. Long-term toxicities attributed to tacrolimus, such as nephrotoxicity and neurotoxicity, can limit the long-term success of tacrolimus in preventing allograft rejection. This article emphasizes the current clinical challenges faced when managing LTx recipients with tacrolimus, offers strategies to manage these issues, and highlights the areas that need further research.
Publisher: Informa UK Limited
Date: 11-2013
Abstract: Replacement therapy with immunoglobulin G (IgG) given as intravenous or subcutaneous (SC) infusions is the standard treatment for patients with primary immunodeficiency. Due to the life-long need for replacement, increased flexibility in the administration and dosage regimens would improve patients' quality of life. A population pharmacokinetic model that can predict plasma IgG concentrations for various routes, dosage regimens, and patient groups is a valuable tool to improve patient therapy. Such a model was developed based on IgG concentrations from 151 unique adult and pediatric patients who participated in 4 clinical trials of intravenous and SC IgG replacement therapy. Simulations predicted that the same total IgG dose, delivered SC, either in 1 biweekly dose (once every 2 weeks), or in 2 weekly doses, results in IgG peak and trough concentrations that remain within ± 10% of each other throughout the 14-day period. The developed population pharmacokinetic model predicted that biweekly SC Hizentra dosing offers a viable alternative to weekly SC therapy, allowing more flexible and optimized dosage regimens for patients with primary immunodeficiency.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 22-08-2017
Publisher: Wiley
Date: 06-08-2012
Publisher: Oxford University Press (OUP)
Date: 14-03-2019
DOI: 10.1093/JAC/DKZ082
Abstract: Antibiotic allergy labels (AALs), reported by up to 25% of hospitalized patients, are a significant barrier to appropriate prescribing and a focus of antimicrobial stewardship (AMS) programmes. A prospective audit of a pharmacist-led AMS penicillin allergy de-labelling ward round at Austin Health (Melbourne, Australia) was evaluated. Eligible inpatients with a documented penicillin allergy receiving an antibiotic were identified via an electronic medical report and then reviewed by a pharmacist-led AMS team. The audit outcomes evaluated were: (i) AMS post-prescription review recommendations (ii) direct de-labelling (iii) inpatient oral rechallenge referral (iv) skin prick testing/intradermal testing referral and (v) outpatient antibiotic allergy clinic assessment. Across a 5 month period, 106 patients were identified from a real-time electronic prescribing antibiotic allergy report. The highest rate of penicillin allergy de-labelling was demonstrated in patients who were referred for an inpatient oral rechallenge with 95.2% (n = 21) successfully having their penicillin AAL removed. From the 22 patients with Type A reactions, 63.6% had their penicillin AAL removed. We demonstrated a significant decrease in the prescribing of restricted antibiotics (defined as third- or fourth-generation cephalosporins, fluoroquinolones, glycopeptides, carbapenems, piperacillin/tazobactam, lincosamides, linezolid or daptomycin) in patients reviewed (pre 42.5% versus post 17.9%, P = 0.0002). A pharmacist-led AMS penicillin allergy de-labelling ward round reduced penicillin AALs and the prescribing of restricted antibiotics. This model could be implemented at other hospitals with existing AMS programmes.
Publisher: SAGE Publications
Date: 16-04-2020
Abstract: It is important for healthcare professional students to understand the experience of people with dementia, their family, and their carers. Despite person-centred educational policies, current curriculums may not adequately prepare students to meet the needs of people with dementia. This study qualitatively evaluated the impact of a virtual dementia experience on medical and pharmacy students’ self-reported knowledge and attitudes towards people with dementia. Ten focus groups were conducted with 29 medical and 24 pharmacy students in September and October 2016. All students had undertaken a multisensory virtual dementia experience designed to simulate the cognitive and perceptual difficulties faced by people with dementia. Focus groups were used to evaluate the virtual dementia experience in terms of perceived usefulness, suggestions for improvement, and ability to inform students’ understanding of dementia-friendly environments. Focus groups were audio-recorded and analysed via a thematic approach. The virtual dementia experience was described as useful and impactful, and students suggested how it could be more tailored towards their learning needs, such as via incorporating hospital, medical, and pharmacy-specific scenarios and opportunities for role play. Additionally, students explained how dementia-friendly communication techniques could be used in their future practice and provided strategies to optimise dementia-friendly characteristics of current work environments. A virtual dementia experience improved student self-reported knowledge and attitudes towards people with dementia.
Publisher: American Society for Microbiology
Date: 2013
DOI: 10.1128/AAC.01463-12
Abstract: Murine models are used to study erythrocytic stages of malaria infection, because parasite morphology and development are comparable to those in human malaria infections. Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models for antimalarials are scarce, despite their potential to optimize antimalarial combination therapy. The aim of this study was to develop a mechanism-based growth model (MBGM) for Plasmodium berghei and then characterize the parasiticidal effect of dihydroartemisinin (DHA) in murine malaria (MBGM-PK-PD). Stage-specific (ring, early trophozoite, late trophozoite, and schizont) parasite density data from Swiss mice inoculated with Plasmodium berghei were used for model development in S-ADAPT. A single dose of intraperitoneal DHA (10 to 100 mg/kg) or vehicle was administered 56 h postinoculation. The MBGM explicitly reflected all four erythrocytic stages of the 24-hour P. berghei life cycle. Merozoite invasion of erythrocytes was described by a first-order process that declined with increasing parasitemia. An efflux pathway with subsequent return was additionally required to describe the schizont data, thus representing parasite sequestration or trapping in the microvasculature, with a return to circulation. A 1-compartment model with zero-order absorption described the PK of DHA, with an estimated clearance and distribution volume of 1.95 liters h −1 and 0.851 liter, respectively. Parasite killing was described by a turnover model, with DHA inhibiting the production of physiological intermediates (IC 50 , 1.46 ng/ml). Overall, the MBGM-PK-PD described the rise in parasitemia, the nadir following DHA dosing, and subsequent parasite resurgence. This novel model is a promising tool for studying malaria infections, identifying the stage specificity of antimalarials, and providing insight into antimalarial treatment strategies.
Publisher: Springer Science and Business Media LLC
Date: 2003
DOI: 10.1067/MCP.2003.9
Publisher: Oxford University Press (OUP)
Date: 30-11-2010
DOI: 10.1093/JAC/DKQ449
Abstract: Infections in critically ill patients continue to result in unacceptably high morbidity and mortality. Although few data exist for correlating antibiotic exposure with outcome, antibiotic dosing is likely to be highly important for maximizing resolution of infection in many patients. The practical and financial difficulties of performing pharmacokinetic (PK) studies in critically ill patients mean that analyses to maximize data such as Monte Carlo simulation (MCS) are highly valuable. MCS uses computer software to perform virtual clinical trials. The building blocks for MCS are: firstly, a robust population PK model from the patient population of interest secondly, descriptors of the effect of covariates that influence the PK parameters thirdly, description of the susceptibility of bacteria to the antibiotic and finally a PK harmacodynamic (PD) target associated with antibiotic efficacy. Probability of target attainment (PTA) outputs can then be generated that describe the proportion of patients that will achieve a pre-specified PD target for an MIC distribution. Such analyses can then inform dosing requirements, which can be used to have a high likelihood of achieving PK/PD targets for organisms with different MICs. In this issue of JAC, Zelenitsky et al. provide a very useful ex le of MCS for interpreting the optimal methods for dosing meropenem, piperacillin/tazobactam, cefepime and ceftobiprole in critically ill patients.
Publisher: Wiley
Date: 07-2011
DOI: 10.1111/J.1445-5994.2009.02160.X
Abstract: Accurate knowledge of the glomerular filtration rate (GFR) is imperative in the intensive care unit (ICU) as renal status is important for medical decisions, including drug dosing. Recently, an estimation of GFR (eGFR) was suggested as a method of estimating GFR. How well this formula predicts GFR in unwell patients with normal initial serum creatinine concentrations has not been examined. The accuracy of the eGFR (before and after adjustment for actual body surface area (BSA)) was compared with measured and with estimated creatinine clearance using the Cockcroft Gault (CG) formula adjusted for total and lean body weight. A total of 237 observations was recorded in 47 subjects. These were initially analysed independently, and then using the first observation only. Overall the mean difference between measured creatinine clearance and eGFR was -12 mL/min (95% confidence interval (CI) -20 to -3), between measured creatinine clearance and CG +17 mL/min (95% CI 9-24), between measured creatinine clearance and CG adjusted for ideal body weight +12 mL/min (95% CI 4-21) and between measured creatinine clearance and eGFR 'unadjusted' for BSA 5 mL/min (95% CI -2-13). Using either eGFR or CG formulae to estimate renal function in ICU subjects with normal serum creatinine concentrations is inaccurate. Although correcting for BSA improves the eGFR, this requirement to measure height and weight removes a major attraction for its use. We suggest that eGFR should not be automatically calculated in the ICU setting.
Publisher: Cambridge University Press (CUP)
Date: 07-2003
DOI: 10.1086/502248
Abstract: This article describes a case of respiratory syncytial virus pneumonia believed to have been acquired nosocomially in an adult renal transplant recipient. The mode of transmission, diagnosis, and prevention of infection due to this virus in the immunocompromised patient are discussed ( Infect Control Hosp Epidemiol 2003 :548-550.
Publisher: Therapeutic Guidelines Limited
Date: 06-2015
DOI: 10.18773/AUSTPRESCR.2015.031
Abstract: The National Return and Disposal of Unwanted Medicines Program provides a free and safe method for the disposal of unwanted and expired medicines. This stops drugs being dumped in landfill and waterways. An audit showed that over 600 tonnes of medicines are returned through the program. A substantial proportion of these medicines were still within their expiry dates. Salbutamol, insulin and frusemide are the most commonly discarded medicines. More than $2 million of public money is wasted each year. Hoarding and non-adherence to treatment contribute to waste. Health professionals may be able to help minimise waste by informing patients about the importance of completing prescribed courses of treatment, and discouraging them from hoarding medicines after reaching the safety net threshold on the Pharmaceutical Benefits Scheme. Prescribe no more than the required quantity of medicines. When starting a new therapy, prescribe a minimal quantity in case the drug is unsuitable for the patient. Advise patients to return all unwanted medicines to a pharmacy for disposal.
Publisher: CSIRO Publishing
Date: 2017
DOI: 10.1071/AH16080
Abstract: Objective The aim of the present study was to describe an environmental framework for pharmacists in primary care in Australia and determine the major factors within that environment that have the greatest bearing on their capacity to implement patient-focused models of professional practice. Methods A draft framework for pharmacists’ practice was developed by allocating structures, systems and related factors known to the researchers or identified from the literature as existing within pharmacists’ internal, operational and external environments to one of five domains: Social, Technological, Economic, Environmental or Political [STEEP]. Focus groups of pharmacists used an adapted nominal group technique to assess the draft and add factors where necessary. Where applicable, factors were consolidated into groups to establish a revised framework. The three major factors or groups in each domain were identified. The results were compared with the enabling factors described in the profession’s vision statement. Results Seventy-eight in idual factors were ultimately identified, with 86% able to be grouped. The three dominant groups in each of the five domains that had a bearing on the implementation of professional models of practice were as follows: (1) Social: the education of pharmacists, their beliefs and the capacity of the pharmacist workforce (2) Technological: current and future practice models, technology and workplace structures (3) Economic: funding of services, the viability of practice and operation of the Pharmaceutical Benefits Scheme (4) Environmental: attitudes and expectations of stakeholders, including consumers, health system reform and external competition and (5) Political: regulation of practice, representation of the profession and policies affecting practice. Conclusions The three dominant groups of factors in each of the five STEEP environmental domains, which have a bearing on pharmacists’ capacity to implement patient-focused models of practice, correlate well with the enabling factors identified in the profession’s vision statement, with the addition of three factors in the Environmental domain of stakeholder attitudes, health system reform and external competition. What is known about the topic? The extensive range of patient-focused professional programs developed for application by pharmacists in primary care in Australia has yet to be widely implemented. What does this paper add? Factors both within and beyond the pharmacists’ immediate practice environment that have a bearing on the uptake of professional programs have been identified and prioritised using a structured thematic approach. What are the implications for practitioners? The results demonstrate the need for a multifactorial approach to the implementation of professional models of practice in this setting.
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.JCHROMB.2010.05.042
Abstract: In this paper, a method for the sensitive and reproducible analysis of lignocaine and its four principal metabolites, monoethylxylidide (MEGX), glycylxylidide (GX), 3-hydroxylignocaine (3-HO-LIG), 4-hydroxylignocaine (4-HO-LIG) in equine urine and plasma s les is presented. The method uses liquid chromatography coupled to tandem mass spectrometry operating in electrospray ionisation positive ion mode (+ESI) via multiple reaction monitoring (MRM). S le preparation involved solid-phase extraction using a mixed-mode phase. The internal standard adopted was lignocaine-d(10). Lignocaine and its metabolites were successfully resolved using an octadecylsilica reversed-phase column using a gradient mobile phase of acetonitrile and 0.1% (v/v) aqueous formic acid at a flow rate of 300 microL/min. Target analytes and the internal standard were determined by using the following transitions lignocaine, 235.2>86.1 3-HO-LIG and 4-HO-LIG, 251.2>86.1 MEGX, 207.1>58.1 GX, 179.1>122.1 and lignocaine-d(10), 245.2>96.1. Calibration curves were generated over the range 1-100 ng/mL for plasma s les and 1-1000 ng/mL for urine s les. The method was validated for instrument linearity, repeatability and detection limit (IDL), method linearity, repeatability, detection limit (MDL), quantitation limit (LOQ) and recovery. The method was successfully used to analyse both plasma and urine s les following a subcutaneous administration of lignocaine to a thoroughbred horse.
Publisher: Springer Science and Business Media LLC
Date: 12-2005
Abstract: It is essential that knowledge gained through health services research is collated and made available for evaluation, for policy purposes and to enable collaboration between people working in similar areas (capacity building). The Australian Quality Use of Medicine (QUM) on-line, web-based project database, known as the QUMmap, was designed to meet these needs for a specific sub-section of health services research related to improving the use of medicines. Australia's National Strategy for Quality Use of Medicines identifies the primacy of consumers as a major principle for quality use of medicines, and aims to support consumer led research. The aim of this study was to determine how consumers as a group have been represented in QUM projects in Australia. A secondary aim was to investigate how the projects with consumer involvement fit into Australia's QUM policy framework. Using the web-based QUMmap, all projects which claimed consumer involvement were identified and stratified into four categories, projects undertaken by (a) consumers for consumers, (b) health professionals for consumers, (c) health professionals for health professionals, and (d) other. Projects in the first two categories were then classified according to the policy 'building blocks' considered necessary to achieve QUM. Of the 143 'consumer' projects identified, the majority stated to be 'for consumers' were either actually by health professionals for health professionals (c) or by health professionals for consumers (b) (47% and 40% respectively). Only 12 projects (9%) were directly undertaken by consumers or consumer groups for consumers (a). The majority of the health professionals for consumers (b) projects were directed at the provision of services and interventions, but were not focusing on the education, training or skill development of consumers. Health services research relating to QUM is active in Australia and the projects are collated and searchable on the web-based interactive QUMmap. Healthcare professionals appear to be dominating nominally 'consumer focussed' research, with less than half of these projects actively involving the consumers or directly benefiting consumers. The QUMmap provides a valuable tool for policy analysis and for provision of future directions through identification of QUM initiatives.
Publisher: Wiley
Date: 19-12-2014
DOI: 10.1111/BCP.12288
Publisher: Oxford University Press (OUP)
Date: 05-03-2009
DOI: 10.1093/JAC/DKP073
Abstract: Dosing of gentamicin in neonates in Christchurch has been carried out since 2000 using a locally developed extended-interval dosing protocol. All dosing data have been recorded in a database. The aims of this study were to analyse the database to determine what percentage of neonates achieved target values for C(max), C(min) and AUC, and to use the pharmacokinetic values of gentamicin to simulate new dosing protocols. C(max), C(min) and AUC were compared with target values. Clearance (CL), volume of distribution (V) and half-life (t(1/2)) were estimated, and used to produce new predictive dosing protocols that were tested and compared with the results of the original protocol. Gentamicin concentrations from 1461 in idual doses were recorded in the database. Four hundred and eight were excluded. Of the remaining 1053, 84% achieved the target C(max) (>10 mg/L), 77% the target C(min) (<1 mg/L) and 63% the target AUC (within 80% to 125%). The number achieving target C(max) and C(min) values was improved markedly by prolonging the dosing intervals, but not by altering the predictive equations. Since the majority of the neonates only received a single dose of gentamicin, a new V-based model was also tested, and performed well. CL (L/kg) increased, while V (L/kg) and t(1/2) (h) both decreased with respect to weight. Extending the dose interval improved the success in achieving target C(max) and C(min), while revision of the dosing equation did not. A V-based model provides an alternative approach to the first dose of gentamicin in neonates.
Publisher: Elsevier BV
Date: 04-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2008
Publisher: BMJ
Date: 05-07-2022
DOI: 10.1136/BMJQS-2021-014185
Abstract: Despite recognition of clinical deterioration and medication-related harm as patient safety risks, the frequency of medication-related Rapid Response System activations is undefined. We aimed to estimate the incidence and preventability of medication-related Medical Emergency Team (MET) activations and describe the associated adverse medication events. A case review study of consecutive MET activations at two acute, academic teaching hospitals in Melbourne, Australia with mature Rapid Response Systems was conducted. All MET activations during a 3-week study period were assessed for a medication cause including identification of the contributing adverse medication event and its preventability, using validated tools and recognised classification systems. There were 9439 admissions and 628 MET activations during the study period. Of these, 146 (23.2%) MET activations were medication related: an incidence of 15.5 medication-related MET activation per 1000 admissions. Medication-related MET activations occurred a median of 46.6 hours earlier (IQR 22-165) in an admission than non-medication-related activations (p=0.001). Furthermore, this group also had more repeat MET activations during their admission (p=0.021, OR=1.68, 95% CI 1.09 to 2.59). A total of 92 of 146 (63%) medication-related MET activations were potentially preventable. Tachycardia due to omission of beta-blocking agents (10.9%, n=10 of 92) and hypotension due to cumulative toxicity (9.8%, n=9 of 92) or inappropriate use (10.9%, n=10 of 92) of antihypertensives were the most common adverse medication events leading to potentially preventable medication-related MET activations. Medications contributed to almost a quarter of MET activations, often early in a patient's admission. One in seven MET activations were due to potentially preventable adverse medication events. The most common of these were omission of beta-blockers and clinically inappropriate antihypertensive use. Strategies to prevent these events would increase patient safety and reduce burden on the MET.
Publisher: Springer Science and Business Media LLC
Date: 06-2017
DOI: 10.1007/S40266-017-0472-8
Abstract: Falls are a leading cause of preventable hospitalizations from long-term care facilities (LTCFs). Polypharmacy and falls-risk medications are potentially modifiable risk factors for falling. This study investigated whether polypharmacy and falls-risk medications are associated with fall-related hospital admissions from LTCFs compared with hospital admissions for other causes. This was a hospital-based, case-control study of patients aged ≥65 years hospitalized from LTCFs. Cases were patients with falls and fall-related injuries, and controls were patients admitted for infections. Conditional logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between polypharmacy (defined as the use of nine or more regular pre-admission medications) and falls-risk medications (categorized as psychotropic medications and those that can cause orthostatic hypotension) with fall-related hospital admissions. There was no association between polypharmacy and fall-related hospital admissions (adjusted OR 0.97, 95% CI 0.63-1.48) however, the adjusted odds of fall-related hospital admissions increased by 16% (95% CI 3-30%) for each additional falls-risk medication. Medications that can cause orthostatic hypotension (adjusted OR 1.25, 95% CI 1.06-1.46), but not psychotropic falls-risk medications (adjusted OR 1.02, 95% CI 0.88-1.18) were associated with fall-related hospital admissions. The association between medications that can cause orthostatic hypotension and fall-related hospital admissions was strongest among residents with polypharmacy (adjusted OR 1.44, 95% CI 1.08-1.92). Polypharmacy was not an independent risk factor for fall-related hospital admissions however, medications that can cause orthostatic hypotension were associated with fall-related hospital admissions, particularly among residents with polypharmacy. Falls-risk should be considered when prescribing medications that can cause orthostatic hypotension.
Publisher: Oxford University Press (OUP)
Date: 28-04-2014
DOI: 10.1093/JAC/DKU120
Abstract: To develop a mechanism-based model that describes the time course of the malaria parasite in infected mice receiving a combination therapy regimen of dihydroartemisinin and piperaquine. Total parasite density-time data from Swiss mice inoculated with Plasmodium berghei were used for the development of population models in S-ADAPT. The mice were administered a single intraperitoneal dose of 30 mg/kg dihydroartemisinin, 10 mg/kg piperaquine phosphate or a combination of both antimalarials at 64 h post-inoculation. In a separate study, mice received multiple dihydroartemisinin doses (5 × 10 mg/kg or 30 mg/kg dihydroartemisinin followed by two 10 mg/kg doses). Parasite recrudescence after treatment was defined using a model that incorporated each erythrocytic stage of the P. berghei life cycle. The disposition of dihydroartemisinin and piperaquine was described by a one-compartment and two-compartment model, respectively. The estimated clearance was 1.95 L/h for dihydroartemisinin and 0.109 L/h for piperaquine. A turnover model described the parasite killing curve after single-agent dosing, with an estimated mean IC50 of 0.747 μg/L for dihydroartemisinin and 16.8 μg/L for piperaquine. In addition, the rate of parasite killing by dihydroartemisinin was almost 50-fold faster than for piperaquine. Parameters from the monotherapy models adequately described the parasite density-time curve following dihydroartemisinin iperaquine combination therapy or multiple-dose regimens of dihydroartemisinin. This study has developed mechanistic models that describe the parasite-time curve after single, multiple or combination dosing of antimalarials to mice. These structural models have potential application for pre-clinical investigations to design and refine artemisinin-based combination therapy dosage regimens.
Publisher: Elsevier BV
Date: 03-2023
DOI: 10.1016/J.SAPHARM.2022.09.014
Abstract: Pharmacist and general practitioner (GP) collaborative models of care are continuing to evolve in the Australian primary care setting. The REMAIN HOME study investigated whether a pharmacist integrated into 14 different primary care teams in general practice (the "practice pharmacist model") reduces readmission to hospital for patients prescribed five or more long term medicines or high risk comorbidities. The aim of this paper is to describe the attitudes of GPs, patients, and practice pharmacists towards this model of pharmacist and GP collaboration. To explore the views and opinions about the model of care (pharmacist integration into general practice), participating GPs were invited to complete a survey that included the 13-item validated Attitudes Toward Collaboration Instrument for GPs (ATCI-GP) one month after the pharmacist had been integrated into the practice. Survey instruments were also created for patients and pharmacist participating in the intervention. These were deployed after the initial consultation and at the end of the intervention period respectively, to elicit each stakeholders' views and experiences of the service. Data were analysed using descriptive statistics. In total, 48 GPs, 43/101 patients (43%) and 11/13 practice pharmacists (85%) completed the survey. The majority of GPs strongly agreed or agreed with all statements of the ATCI-GP, indicating support for the practice-integrated pharmacist model. Most patients agreed that there was a role for a pharmacist in their general practice (n = 28, 76%), and that they would like to see the pharmacist again (n = 34, 79%). Pharmacists indicated that they enjoyed the role (n = 11, 91%) and found the position professionally satisfying (n = 9, 82%). Most pharmacists agreed that co-location (inside the general practice itself, rather than in a co-located pharmacy) was beneficial (n = 8, 73%) and all pharmacists (100%) acknowledged the benefits of having access to patient medical records. Free text comments from GPs were enthusiastic overall, although some concerns about the financial viability of the model in the current setting were raised. The primary limitation of the study is the anonymous nature of the survey, meaning clustering of responses across the 14 sites could not be determined. A practice pharmacist model of care in the Australian primary care setting appears to be accepted by GPs, patients and practice pharmacists and provides promising evidence that this model of care is likely to be well accepted if implemented more broadly in the Australian healthcare setting, provided that it can be appropriately remunerated.
Publisher: Wiley
Date: 25-01-2016
DOI: 10.1111/JEP.12514
Abstract: The prevalence of polypharmacy in residential aged care facilities (RACFs) is high and increasing. Although not necessarily inappropriate, polypharmacy has been associated with drug interactions, adverse drug events, geriatric syndromes and hospital admissions. The aim of this study was to identify and prioritize factors contributing to the increasing prevalence of polypharmacy in RACFs. Seventeen health care professionals from metropolitan and regional Victoria and South Australia identified and prioritized factors using a modified nominal group technique. The top five factors ranked from most important to fifth most important were 'changes in resident mix', 'increasing numbers of prescribers and the reluctance of one prescriber to discontinue a medicine commenced by another prescriber', 'better adherence to clinical practice guidelines', 'increasing reliance on locums' and 'greater recognition and pharmacological management of pain'. Reasons for the increase in polypharmacy are multifactorial. Understanding the factors contributing to polypharmacy may help to guide future research and develop interventions to manage polypharmacy in RACFs.
Publisher: MDPI AG
Date: 13-01-2022
DOI: 10.3390/ANTIBIOTICS11010101
Abstract: We evaluated piperacillin-tazobactam and tobramycin regimens against Pseudomonas aeruginosa isolates from critically ill patients. Static-concentration time-kill studies (SCTK) assessed piperacillin-tazobactam and tobramycin monotherapies and combinations against four isolates over 72 h. A 120 h-dynamic in vitro infection model (IVM) investigated isolates Pa1281 (MICpiperacillin 4 mg/L, MICtobramycin 0.5 mg/L) and CR380 (MICpiperacillin 32 mg/L, MICtobramycin 1 mg/L), simulating the pharmacokinetics of: (A) tobramycin 7 mg/kg q24 h (0.5 h-infusions, t1/2 = 3.1 h) (B) piperacillin 4 g q4 h (0.5 h-infusions, t1/2 = 1.5 h) (C) piperacillin 24 g/day, continuous infusion A + B A + C. Total and less-susceptible bacteria were determined. SCTK demonstrated synergy of the combination for all isolates. In the IVM, regimens A and B provided initial killing, followed by extensive regrowth by 72 h for both isolates. C provided log10 CFU/mL killing, followed by regrowth close to initial inoculum by 96 h for Pa1281, and suppressed growth to log10 CFU/mL for CR380. A and A + B initially suppressed counts of both isolates to log10 CFU/mL, before regrowth to control or starting inoculum and resistance emergence by 72 h. Overall, the combination including intermittent piperacillin-tazobactam did not provide a benefit over tobramycin monotherapy. A + C, the combination regimen with continuous infusion of piperacillin-tazobactam, provided synergistic killing (counts log10 CFU/mL) of Pa1281 and CR380, and suppressed regrowth to and log10 CFU/mL, respectively, and resistance emergence over 120 h. The shape of the concentration–time curve was important for synergy of the combination.
Publisher: Informa UK Limited
Date: 10-03-2020
Publisher: Springer Science and Business Media LLC
Date: 11-10-2018
DOI: 10.1007/S00520-017-3915-1
Abstract: Defibrotide is an agent used to treat sinusoidal obstruction syndrome (SOS/VOD) in patients undergoing haemopoietic stem cell transplantation. The aim of this study was to evaluate the effectiveness of defibrotide used within institutional guidelines for the treatment of SOS/VOD in patients undergoing haemopoietic stem cell transplantation (HSCT). Data for 23 patients was retrospectively reviewed to evaluate the effectiveness of defibrotide and the utility of response criteria to direct therapy as specified within institution guidelines. Patients met institutional criteria for a diagnosis of SOS/VOD based on predominantly Baltimore criteria and received defibrotide. Stabilisation or improvement in symptoms and biochemical markers was required for continuation of therapy with defibrotide. Overall, 14 patients responded to therapy. Survival at day 100 post HSCT was 70%. Median serum (total) bilirubin concentrations in all evaluable patients had decreased at days 5 and 10 (p < 0.001). There was a proportional reduction in median weight of 4% by day 5 and 6.6% by day 10 (p < 0.001). On cessation of defibrotide, there was a decrease in the proportion of patients exhibiting hepatomegaly (p = 0.02), ascites (p < 0.01) and requiring oxygen supplementation (p < 0.01), with 70% survival at day 100 post HSCT. Defibrotide to treat SOS/VOD and continued based on attainment of early response was effective management of this condition. Defibrotide should be considered in any consensus protocol providing guidance on the management of SOS/VOD, with future studies considered to assess appropriate time points for response to therapy during treatment.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.TOXICON.2008.08.013
Abstract: Many snake venoms contain procoagulant toxins that activate the coagulation cascade and cause venom-induced consumptive coagulopathy (VICC). We developed a semi-mechanistic model of the clotting cascade in order to explore the effects of the procoagulant toxin from taipan venom on this system as well as the effects of antivenom. Simulations of the time course in the change of clotting factors were compared to data collected from taipan envenomed patients. The model accurately predicted the observed concentration of clotting factors over time following taipan envenomation. Investigations from the model indicated that the upper limit of the half-life of the procoagulant toxin was 1h. Simulations from the model also suggest that antivenom for Australasian elapids has negligible effect on reducing the recovery time of the coagulation profile unless administered almost immediately after envenomation. The model has generality to be expanded to describe the effects of other venoms and drugs on the clotting cascade.
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.JCHROMB.2009.08.037
Abstract: In this manuscript, we present a simple and reliable method for the quantitation of para-aminohippuric acid (PAH 2-(4-aminobenzamido)acetic acid) in human plasma and urine using liquid chromatography coupled to electrospray ionisation low-energy collision-induced dissociation tandem mass spectrometry (HPLC-ESI-CID-MS/MS) analysis (negative ion mode) via multiple reaction monitoring (MRM). S le preparation involved protein precipitation of plasma s les with acetonitrile and subsequent dilution of urine s les with the mobile phase. The internal standard (IS) adopted was para-aminosalicylic acid (PAS 4-amino-2-hydroxybenzoic acid). Chromatographic separation was achieved on a Cosmosil HILIC column using an isocratic mobile phase consisting of ammonium acetate buffer (20mM) and acetonitrile (45:55, v/v) at a flow rate of 200microl/min. The transactions monitored were m/z 192.9-->149.1 for PAH and m/z 152.1-->108.1 for IS. Linear calibration curves were generated over the PAH concentration range of 0.2-100mg/L in human plasma and urine. The method was validated for selectivity, accuracy, precision, recovery and stability according to USFDA criteria, and has been successfully applied to a pharmacokinetic study in healthy volunteers administered an intravenous dose of 440mg PAH.
No related grants have been discovered for Carl Kirkpatrick.