ORCID Profile
0000-0003-3888-7287
Current Organisation
University of South Australia
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Publisher: Oxford University Press (OUP)
Date: 14-08-2019
DOI: 10.1111/JPHP.13154
Abstract: The selection of s le times for a pharmacokinetic study is important when trapezoidal integration (e.g. non-compartmental analysis) is used to determine the area under the concentration–time curve (AUC). The aim of this study was to develop an algorithm that determines optimal times that provide the most accurate AUC by minimising trapezoidal integration error. The algorithm required initial single in idual or mean pooled concentration data but did not specifically require a prior pharmacokinetic model. Optimal s le intervals were determined by minimising trapezoidal error using a genetic algorithm followed by a quasi-Newton method. The method was evaluated against simulated and clinical datasets to determine the method's ability to estimate the AUC. The s le times produced by the algorithm were able to accurately estimate the AUC of pharmacokinetic profiles, with the relative AUC having 90% confidence intervals of 0.919–1.05 for profiles with two-compartment kinetics. When comparing the algorithm with rich s ling (e.g. phase I trial), the algorithm provided equivalent or superior s le times with fewer observations. The creation of the algorithm and its companion web application allows users with limited pharmacometric or programming training can obtain optimal s ling times for pharmacokinetic studies.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2016
DOI: 10.1007/S40262-016-0394-3
Abstract: Tyrosine kinase inhibitors have been marketed as a fixed dose, 'one size fits all' treatment strategy. Physicians have also been interested in this method of dosing, knowing the complex planning of other current cancer therapies administered on a mg/m(2) or mg/kg basis and subsequent occurrence of dosing error or concern for underdosing. The 'simple and safe' strategy of a single dose of tyrosine kinase inhibitor for cancer has thus been widely adopted. However, the benefits purported to exist in the clinical trials do not appear to be borne out in clinical practice, particularly in solid tumours. In order to investigate whether pharmacokinetic variability is a contributor to the variable outcomes, pharmacokinetic targets to enable in idualisation of tyrosine kinase inhibitor administration are now emerging. Evidence suggests there is not a clear relationship of a single dose to maximum plasma concentration (C max), steady-state trough concentration (C trough) or area under the curve (AUC). Furthermore, a significant number of questions remain related to the specific timing and frequency of s le collection required to achieve optimal outcomes. This article reviews the wide variability in the literature on this topic, specifically the different pharmacokinetic targets of the same drug for different cancers, for different states of cancer, and changing pharmacokinetic parameters over a treatment interval in cancer. It appears the optimal s ling times to enable appropriate dose recommendations across patients and diseases may vary, and are not always trough concentrations at steady state. Importantly, the need to be pragmatic in a clinical setting is paramount. Lastly, international collaborations to increase s le size are highly recommended to ensure enough patients are s led to be sure of a clinical benefit from this concentration-directed methodology.
Publisher: SAGE Publications
Date: 09-09-2008
Abstract: l-carnitine is an endogenous substance, vital in the transport of fatty acids across the inner mitochondrial membrane for oxidation. Disturbances in carnitine homeostasis can have a significant impact on human health therefore, it is critical to define normal endogenous concentrations for l-carnitine and its esters to facilitate the diagnosis of carnitine deficiency disorders. This study was conducted to determine the normal concentrations of a number of carnitines in healthy adults using three analytical methods. The impact of age and gender on carnitine concentrations was also examined. Blood s les were collected from 60 healthy subjects of both genders and various ages. Plasma s les were analysed for endogenous carnitine concentrations by radioenzymatic assay, high-performance liquid chromatography and electrospray tandem mass spectrometry. Precision and accuracy of results obtained for each assay were within acceptable limits. Average endogenous concentrations obtained from the three analytical methods in this study were in the range of 38–44, 6–7 and 49–50 μmol/L for l-carnitine, acetyl-l-carnitine and total carnitine, respectively. Comparison of results between the genders indicated that males had significantly higher endogenous plasma l-carnitine and total carnitine concentrations than females. Age was found to have no impact on plasma carnitine concentrations. These results are useful in the evaluation of biochemical or metabolic disturbances and in the diagnosis and treatment of patients with carnitine deficiency.
Publisher: Wiley
Date: 12-07-2008
DOI: 10.1111/J.1440-1797.2007.00817.X
Abstract: It has been widely established that patients with end-stage renal disease undergoing chronic haemodialysis therapy exhibit low endogenous levels of L-carnitine and elevated acylcarnitine levels however, the clinical implication of this altered carnitine profile is not as clear. It has been suggested that these disturbances in carnitine homeostasis may be associated with a number of clinical problems common in this patient population, including erythropoietin-resistant anaemia, cardiac dysfunction, and dialytic complications such as hypotension, cr s and fatigue. In January 2003, the Centers for Medicare and Medicaid Services (USA) implemented coverage of intravenous L-carnitine for the treatment of erythropoietin-resistant anaemia and/or intradialytic hypotension in patients with low endogenous L-carnitine concentrations. It has been estimated that in the period of 1998-2003, 3.8-7.2% of all haemodialysis patients in the USA received at least one dose of L-carnitine, with 2.7-5.2% of patients receiving at least 3 months of supplementation for one or both of these conditions. The use of L-carnitine within Australia is virtually non-existent, which leads us to the question: Are Australian haemodialysis patients missing out? This review examines the previous research associated with L-carnitine administration to chronic dialysis patients for the treatment of anaemia, cardiac dysfunction, dyslipidaemia and/or dialytic symptoms, and discusses whether supplementation is warranted within the Australian setting.
Publisher: Wiley
Date: 08-06-2020
DOI: 10.1111/BCP.14372
Abstract: There are few fields of medicine in which the in idualisation of medicines is more important than in the area of oncology. Under‐dosing can have significant ramifications due to the potential for therapeutic failure and cancer progression by contrast, over‐dosing may lead to severe treatment‐limiting side effects, such as agranulocytosis and neutropenia. Both circumstances lead to poor patient prognosis and contribute to the high mortality rates still seen in oncology. The concept of dose in idualisation tailors dosing for each in idual patient to ensure optimal drug exposure and best clinical outcomes. While the value of this strategy is well recognised, it has seen little translation to clinical application. However, it is important to recognise that the clinical setting of oncology is unlike that for which therapeutic drug monitoring (TDM) is currently the cornerstone of therapy (e.g. antimicrobials). Whilst there is much to learn from these established TDM settings, the challenges presented in the treatment of cancer must be considered to ensure the implementation of TDM in clinical practice. Recent advancements in a range of scientific disciplines have the capacity to address the current system limitations and significantly enhance the use of anticancer medicines to improve patient health. This review examines opportunities presented by these innovative scientific methodologies, specifically s ling strategies, bioanalytics and dosing decision support, to enable optimal practice and facilitate the clinical implementation of TDM in oncology.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2022
DOI: 10.1097/FTD.0000000000000944
Abstract: In idualization of vancomycin dosing based on therapeutic drug monitoring (TDM) data is known to improve patient outcomes compared with fixed or empirical dosing strategies. There is increasing evidence to support area-under-the-curve (AUC 24 )–guided TDM to inform vancomycin dosing decisions for patients receiving therapy for more than 48 hours. It is acknowledged that there may be institutional barriers to the implementation of AUC 24 -guided dosing, and additional effort is required to enable the transition from trough-based to AUC 24 -based strategies. Adequate documentation of s ling, correct storage and transport, accurate laboratory analysis, and pertinent data reporting are required to ensure appropriate interpretation of TDM data to guide vancomycin dosing recommendations. Ultimately, TDM data in the clinical context of the patient and their response to treatment should guide vancomycin therapy. Endorsed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology, the IATDMCT Anti-Infectives Committee, provides recommendations with respect to best clinical practice for vancomycin TDM.
Publisher: Oxford University Press (OUP)
Date: 11-11-2020
DOI: 10.1093/JAC/DKZ476
Abstract: Cefepime-induced neurotoxicity (CIN) has been demonstrated to be associated with cefepime plasma concentrations however, the toxicity threshold remains unclear. The primary objective of this study was to identify the cefepime plasma trough concentration at which neurotoxicity occurs. Secondary objectives were to determine the incidence of CIN at a large tertiary institution and to identify patient factors associated with the development of CIN. A retrospective review of all adult patients administered cefepime between October 2017 and May 2018 in a tertiary hospital was conducted to determine total incidence of CIN. A receiver operating characteristic (ROC) curve was constructed to review the sensitivity and specificity of using various cefepime trough plasma concentrations to predict the development of neurotoxicity. Cefepime plasma concentrations were measured using ultra-HPLC. A regression was conducted to identify patient factors associated with CIN. In total, 206 patients were administered 259 courses of cefepime, with an overall CIN incidence of 6% (16/259 courses). A total of 64 courses had a cefepime trough concentration measured (24.7%). A cefepime trough concentration of 36 mg/L provided the best differentiation between patients who experienced neurotoxicity and those who did not. No other patient covariates were identified to be significantly associated with neurotoxicity occurring. A cefepime trough plasma concentration ≥36 mg/L appears to be the most sensitive and specific cut-off to predict CIN occurring. No patient factors were associated with the development of CIN when accounting for cefepime trough plasma concentrations.
Publisher: SAGE Publications
Date: 09-2005
Abstract: Background: Patients with end-stage renal disease (ESRD) undergoing long-term haemodialysis exhibit low L-carnitine and elevated acylcarnitine concentrations. This study evaluated endogenous concentrations of an array of acylcarnitines (carbon chain length up to 18) in healthy in iduals and ESRD patients receiving haemodialysis, and examined the impact of a single haemodialysis session on acylcarnitine concentrations. Methods: Blood s les were collected from 60 healthy subjects and 50 ESRD patients undergoing haemodialysis (pre- and post-dialysis s les). Plasma s les were analysed for in idual acylcarnitine concentrations by electrospray MS/MS. Results: Of the 31 acylcarnitines, 29 were significantly ( P .05) elevated in ESRD patients compared with healthy controls in particular, C5 and C8:1 concentrations were substantially elevated. For acylcarnitines with a carbon chain length less than eight, plasma acylcarnitine concentrations decreased significantly over the course of a single dialysis session however, post-dialysis concentrations invariably remained significantly higher than those in healthy subjects. Dialytic removal of acylcarnitines diminished once the acyl chain length exceeded eight carbons. Conclusions: The accumulation of acylcarnitines during long-term haemodialysis suggests that removal by haemodialysis is less efficient than removal from the body by the healthy kidney. Removal is significantly correlated to acyl chain length, most likely due to the increased molecular weight and lipophilicity that accompanies increased chain length.
Publisher: Oxford University Press (OUP)
Date: 16-11-2019
DOI: 10.1093/JAC/DKY466
Abstract: Ribavirin is used in the treatment of respiratory paramyxovirus infection in lung transplant recipients however, its pharmacokinetic profile in the transplant population is unknown despite the potential for alterations due to underlying pathology. Furthermore, the ability of current regimens to meet exposure targets has not been established. This study examined the pharmacokinetics of ribavirin in a lung transplant population for which current and alternative dosing regimens were assessed. Population pharmacokinetic modelling was conducted in NONMEM using concentration-time data from 24 lung transplant recipients and 6 healthy volunteers. Monte Carlo simulation was used to assess the ability of dosing regimens to achieve pre-specified target concentrations. A three-compartment model with first-order elimination most adequately described ribavirin concentration-time data, with CLCR and patient type (i.e. lung transplant) identified as significant covariates in the model. Simulations indicate that current regimens achieve efficacious concentrations within 24 h of treatment initiation that increase to supra-therapeutic levels over the treatment period. A regimen of 8 mg/kg q6h orally for 48 h followed by 8 mg/kg q24h orally for the remainder of the treatment period was predicted to result in >90% of patients exhibiting concentrations within the defined target range throughout the entire treatment course. Additional work to formally establish target therapeutic concentrations is required however, this study provides a valuable first step in determining optimal ribavirin treatment regimens for paramyxovirus infections in the lung transplant population.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2023
DOI: 10.1097/FTD.0000000000001047
Abstract: Different software applications have been developed to support health care professionals in in idualized drug dosing. However, their translation into clinical practice is limited, partly because of poor usability and integration into workflow, which can be attributed to the limited involvement of health care professionals in the development and implementation of drug dosing software. This study applied codesign principles to inform the design of a drug dosing software to address barriers in therapeutic drug monitoring using vancomycin as an ex le. Three workshops (face-to-face and online) were conducted by design researchers with pharmacists and prescribers. User journey storyboards, user personas, and prototyping tools were used to explore existing barriers to practice and opportunities for innovation through drug dosing software design. A prototype of the software interface was developed for further evaluation. Health care professionals (11 hospital pharmacists and 6 prescribers) with ≥2 years of clinical experience were recruited. Confidence and software usability emerged as the main themes. Participants identified a lack of confidence in vancomycin dosing and pharmacokinetic understanding and difficulty in accessing practice guidelines as key barriers that could be addressed through software implementation. Accessibility to information (eg, guidelines and pharmacokinetic resources) and information presentation (eg, graphical) within the dosing software were dependent on the needs and experience of the user. A software prototype with a speedometer-dial visual to convey optimal doses was well received by participants. The perspectives of health care professionals highlight the need for drug dosing software to be user centered and adaptable to the needs and workflow of end users. Continuous engagement with stakeholders on tool usability, training, and education is needed to promote the implementation in practice.
Publisher: Wiley
Date: 02-2023
DOI: 10.1111/BCP.15668
Abstract: Dose‐prediction software is recommended to enable area under the curve over 24 h (AUC 24 )‐guided dosing of the antibiotic vancomycin. However, uncertainty remains about how best to implement software in the clinic. We describe the activity, over 18 months, of a consultative therapeutic drug monitoring Advisory Service (the Service) for vancomycin that used dose‐prediction software alongside clinical expertise, identifying factors that influence attainment of therapeutic targets. Of the 408 vancomycin dose reports provided for 182 courses of therapy, most (57%) recommended a dose change. The majority (82.8%, 193/233) of recommended dose adjustments were accepted by treating teams. A dose report was not published for 125 courses of therapy, with reasons including patient in intensive care unit or service error. An estimated 26.6 h of staff time was allocated to Service activities each month. Publication of a dose report facilitated attainment of therapeutic targets ( P = .002). Software integration could improve Service outcomes, avoiding errors and reducing staff workload.
Publisher: Wiley
Date: 26-04-2021
DOI: 10.1111/BCP.14856
Abstract: The consumption of caffeine has been linked to osteoporosis, believed to be due to enhanced bone resorption as a result of increased calcium excretion in the urine. However, the amount of calcium in the urine may not necessarily reflect the true effect of caffeine on calcium clearance. This study therefore examined the impact of high‐dose, short‐term caffeine intake on renal clearance of calcium, sodium and creatinine in healthy adults. In a double‐blind clinical study, participants chewed caffeine ( n = 12) or placebo ( n = 12) gum for 5 minutes at 2‐hour intervals over a 6‐hour treatment period (800 mg total caffeine). Caffeine increased renal calcium clearance by 77%. Furthermore, the effect was positively correlated with sodium clearance and urine volume, suggesting that caffeine may act through inhibition of sodium reabsorption in the proximal convoluted tubule. This study confirmed that caffeine does increase renal calcium clearance and fosters further investigation into safe consumption of caffeine.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.CLINTHERA.2017.12.008
Abstract: Medicinal cannabis is prescribed under the provision of a controlled drug in the Australian Poisons Standard. However, multiple laws must be navigated in order for patients to obtain access and imported products can be expensive. Dose-response information for both efficacy and toxicity pertaining to medicinal cannabis is lacking. The pharmacokinetic properties of cannabis administered by traditional routes has been described but to date, there is no literature on the pharmacokinetic properties of an intraperitoneal cannabinoid emulsion. A cachectic 56-year-old female with stage IV ovarian cancer and peritoneal metastases presented to hospital with fevers, abdominal distension and severe pain, vomiting, anorexia, dehydration and confusion. The patient reported receiving an intraperitoneal injection, purported to contain 12g of mixed cannabinoid (administered by a deregistered medical practitioner) two days prior to presentation. Additionally, cannabis oil oral capsules were administered in the hours prior to hospital admission. THC concentrations were consistent with the clinical state but not with the known pharmacokinetic properties of cannabis nor of intraperitoneal absorption. THC concentrations at the time of presentation were predicted to be ~60ng/mL. Evidence suggests that blood THC concentrations >5ng/mL are associated with substantial cognitive and psychomotor impairment. The predicted time for concentrations to drop <5ng/mL was 49days after administration. The unusual pharmacokinetic properties of the case suggest that there is a large amount unknown about cannabis pharmacokinetic properties. The pharmacokinetic properties of a large amount of a lipid soluble compound given intraperitoneally gave insights into the absorption and distribution of cannabinoids, particularly in the setting of metastatic malignancy.
Publisher: Oxford University Press (OUP)
Date: 04-11-2014
DOI: 10.1093/JAC/DKU430
Abstract: The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic harmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate. Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM. A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration-time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life (407 versus 566 h) and T>MIC (766 versus 893 h). This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy in iduals and patients. As VC/F is related to the earlier portion of the concentration-time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/F.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2019
DOI: 10.1097/FTD.0000000000000690
Abstract: Vancomycin pharmacokinetics are best described using a 2-compartment model. However, 1-compartment population models are commonly used as the basis for dose prediction software. Therefore, the validity of using a 1-compartment model to guide vancomycin drug dosing was examined. Published plasma concentration–time data from adult subjects (n = 30) with stable renal function administered a single intravenous infusion of vancomycin were extracted from previous studies. The vancomycin area under the curve (AUC 0–∞ ) was calculated for each subject using noncompartmental methods (AUC NCA ) and by fitting 1- (AUC 1CMT ), 2- (AUC 2CMT ), and 3- (AUC 3CMT ) compartment infusion models. The optimal model fit was determined using the Akaike information criterion and visual inspection of the residual plots. The in idual compartmental AUC 0–∞ values from the 1- and 2-compartment models were compared with AUC NCA values using one-way repeated measures analysis of variance. The mean (±SD) AUC estimates were similar for the different methods: AUC NCA 180 ± 86 mg·h/L, AUC 1CMT 167 ± 79 mg·h/L, and AUC 2CMT 183 ± 88 mg·h/L. Despite the overlapping AUC values, AUC 2CMT and AUC NCA were significantly greater than AUC 1CMT ( P 0.05). The 3-compartment model was excluded from the analysis because of the failure to converge in some instances. Dose prediction software using a 1-compartment model as the basis for Bayesian forecasting underestimates drug exposure (estimated as the AUC) by less than 10%. This is unlikely to be clinically significant with respect to dose adjustment. Therefore, a 1-compartment model may be sufficient to guide vancomycin dosing in adult patients with stable renal function.
Publisher: American Society for Microbiology
Date: 18-01-2022
DOI: 10.1128/AAC.01584-21
Abstract: Despite repeated malaria infection, in iduals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy.
Publisher: Wiley
Date: 05-12-2019
DOI: 10.1002/PSP4.12364
Publisher: Mary Ann Liebert Inc
Date: 10-2022
Publisher: Wiley
Date: 19-01-2011
DOI: 10.1111/J.1365-2796.2010.02341.X
Abstract: The underlying aetiology of chronic fatigue syndrome is currently unknown however, in the light of carnitine's critical role in mitochondrial energy production, it has been suggested that chronic fatigue syndrome may be associated with altered carnitine homeostasis. This study was conducted to comparatively examine full endogenous carnitine profiles in patients with chronic fatigue syndrome and healthy controls. A cross-sectional, observational study. Forty-four patients with chronic fatigue syndrome and 49 age- and gender-matched healthy controls were recruited from the community and studied at the School of Pharmacy & Medical Sciences, University of South Australia. All participants completed a fatigue severity scale questionnaire and had a single fasting blood s le collected which was analysed for l-carnitine and 35 in idual acylcarnitine concentrations in plasma by LC-MS/MS. Patients with chronic fatigue syndrome exhibited significantly altered concentrations of C8:1, C12DC, C14, C16:1, C18, C18:1, C18:2 and C18:1-OH acylcarnitines of particular note, oleyl-L-carnitine (C18:1) and linoleyl-L-carnitine (C18:2) were, on average, 30-40% lower in patients than controls (P < 0.0001). Significant correlations between acylcarnitine concentrations and clinical symptomology were also demonstrated. It is proposed that this disturbance in carnitine homeostasis is reflective of a reduction in carnitine palmitoyltransferase-I (CPT-I) activity, possibly a result of the accumulation of omega-6 fatty acids previously observed in this patient population. It is hypothesized that the administration of omega-3 fatty acids in combination with l-carnitine would increase CPT-I activity and improve chronic fatigue syndrome symptomology.
Publisher: Informa UK Limited
Date: 04-05-2022
DOI: 10.1080/17425255.2022.2098106
Abstract: Vancomycin dosing decisions are informed by factors such as body weight and renal function. It is important to understand the impact of obesity on vancomycin pharmacokinetics and how this may influence dosing decisions. Vancomycin dosing guidelines use varied descriptors of body weight and renal function. There is uncertainty whether current dosing guidelines result in attainment of therapeutic targets in obese in iduals. Literature was explored using PubMed, Embase, and Google Scholar for articles from January 1980 to July 2021 regarding obesity-driven physiological changes, their influence on vancomycin pharmacokinetics and body size descriptors and renal function calculations in vancomycin dosing. Pharmacokinetic simulations reflective of international vancomycin dosing guidelines were conducted to evaluate the ability of using total, ideal, and adjusted body weight, as well as Cockcroft-Gault and CKD-EPI equations to attain an area-under-the-curve to minimum inhibitory concentration ratio (AUC Vancomycin pharmacokinetics in obese in iduals remains debated. Guidelines that determine loading doses using total body weight, and maintenance doses adjusted based on renal function and adjusted body weight, may be most appropriate for obese in iduals. Use of ideal body weight leads to subtherapeutic vancomycin exposure and underestimation of renal function.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2019
Publisher: Oxford University Press (OUP)
Date: 13-08-2020
DOI: 10.1093/JAC/DKAA320
Abstract: Current guidelines for intravenous vancomycin identify drug exposure (as indicated by the AUC) as the best pharmacokinetic (PK) indicator of therapeutic outcome. To assess the accuracy of two Bayesian forecasting programs in estimating vancomycin AUC0–∞ in adults with limited blood concentration s ling. The application of seven vancomycin population PK models in two Bayesian forecasting programs was examined in non-obese adults (n = 22) with stable renal function. Patients were intensively s led following a single (1000 mg or 15 mg/kg) dose. For each patient, AUC was calculated by fitting all vancomycin concentrations to a two-compartment model (defined as AUCTRUE). AUCTRUE was then compared with the Bayesian-estimated AUC0–∞ values using a single vancomycin concentration s led at various times post-infusion. Optimal s ling times varied across different models. AUCTRUE was generally overestimated at earlier s ling times and underestimated at s ling times after 4 h post-infusion. The models by Goti et al. (Ther Drug Monit 2018 212–21) and Thomson et al. (J Antimicrob Chemother 2009 1050–7) had precise and unbiased s ling times (defined as mean imprecision & % and & mg·h/L, with 95% CI for mean bias containing zero) between 1.5 and 6 h and between 0.75 and 2 h post-infusion, respectively. Precise but biased s ling times for Thomson et al. were between 4 and 6 h post-infusion. When using a single vancomycin concentration for Bayesian estimation of vancomycin drug exposure (AUC), the predictive performance was generally most accurate with s le collection between 1.5 and 6 h after infusion, though optimal s ling times varied across different population PK models.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.IJANTIMICAG.2021.106443
Abstract: Cefepime-induced neurotoxicity (CIN) is an increasingly reported adverse event however, the toxicity threshold remains unclear. This study was conducted to provide a comprehensive examination of the most appropriate threshold for CIN, and evaluate the ability of current dosing regimens to attain therapeutic targets. Data of the incidence of CIN and cefepime plasma concentrations were collected retrospectively from patients administered cefepime. Population pharmacokinetic modelling was used to determine daily cefepime trough concentration (C In total, 102 cefepime courses were evaluated, with CIN reported in 10. ROC analyses showed that all cefepime pharmacokinetic parameters were strongly predictive of CIN. C The findings from this study provide evidence that cefepime exposure is highly predictive of CIN, with C
Publisher: Elsevier BV
Date: 05-2023
Publisher: BMJ
Date: 20-08-2012
Publisher: Elsevier BV
Date: 10-2004
Publisher: Springer Science and Business Media LLC
Date: 21-08-2015
DOI: 10.1007/S40261-015-0312-8
Abstract: Piperaquine-dihydroartemisinin combination therapy has established efficacy for the treatment of malaria however, a more comprehensive understanding of the pharmacokinetic properties and factors contributing to inter- and intra-in idual variability is critical to optimize clinical use. This study assessed the effects of food on the pharmacokinetics of combination piperaquine-dihydroartemisinin administration in healthy volunteers. This was an open-label, single-dose, parallel-group study. Participants were randomly allocated to receive oral piperaquine-dihydroartemisinin either after an overnight fast or immediately after a standardized, high-fat, high-calorie meal. Blood s les were collected for analysis of plasma piperaquine and dihydroartemisinin concentrations, which were utilized for calculation of pharmacokinetic parameters, using a standard model-independent approach. Consumption of a high-fat, high-calorie meal resulted in substantial increases in the extent of exposure to piperaquine (ratio between area under the plasma concentration-time curve [AUC] values from 0 to 168 h in the fed and fasted states [AUC0-168 h FED/AUC0-168 h FASTED] = 299 %, 90 % confidence interval [CI] 239-374 %). This likely reflects an increase in the oral bioavailability of the drug, directly related to the fat content of the meal. Co-administration of food was also found to result in both delayed and enhanced absorption of dihydroartemisinin (ratio between AUC values from time zero to infinity in the fed and states [AUC∞ FED/AUC∞ FASTED] = 142 %, 90 % CI 113-178 % ratio between mean transit time [MTT] values in the fed and fasted states [MTTFED/MTTFASTED] = 135 %, 90 % CI 114-160 %). Although food was found to significantly impact on the pharmacokinetics of piperaquine and dihydroartemisinin, given the low fat content of standard meals within endemic regions and the anorexic effects of malaria infection, these results are unlikely to impact on the clinical utility of these drugs. However, co-administration of food with these anti-malarials by populations consuming a typical Western diet should be avoided to reduce the risk of toxic side effects. It is therefore a general recommendation that piperaquine-dihydroartemisinin not be administered within ±3 h of food consumption.
Publisher: Oxford University Press (OUP)
Date: 08-10-2009
DOI: 10.1093/NDT/GFN588
Abstract: Anaemia is a common complication associated with haemodialysis and is usually managed by treatment with recombinant human erythropoietin (rHuEPO). However, many patients remain hyporesponsive to rHuEPO treatment despite adequate iron therapy. The effect of L-carnitine administration on rHuEPO dose and/or haematocrit in haemodialysis patients has been previously reported with equivocal results. This study examined the relationship between endogenous carnitine pool composition and rHuEPO requirements in long-term haemodialysis patients. Pre-dialysis blood s les were collected from 87 patients and analysed for plasma L-carnitine and in idual acylcarnitine levels by LCMS/MS. As an indication of rHuEPO responsiveness, erythropoietin resistance index (ERI) was calculated as rHuEPO dose/kg/week normalized for haemoglobin levels. A significant negative correlation between L-carnitine levels and ERI was found (P = 0.0421). All patients categorized as high ERI (>0.02 microg/kg/week/gHb) exhibited subnormal L-carnitine levels ( 30 microM) displayed low ERI values (<0.02 microg/kg/week/gHb). More importantly, the ratio of non-acetyl acylcarnitines/total carnitine was significantly positively correlated with ERI (P = 0.0062). These data illustrate the relationship between carnitine levels and response to rHuEPO treatment in haemodialysis patients, in particular, the importance of the proportion of long-chain acylcarnitines within the plasma carnitine pool. This proportion may be more indicative of the response to L-carnitine supplementation than absolute L-carnitine levels alone.
Publisher: BMJ
Date: 20-12-2022
Publisher: Wiley
Date: 05-12-2021
DOI: 10.1002/CPT.2113
Abstract: This study evaluated the ability of a pilot therapeutic drug monitoring (TDM) Advisory Service to facilitate vancomycin therapeutic target attainment within a real‐world clinical setting. The Service provided area under the concentration‐time curve (AUC)–guided vancomycin dose recommendations, using Bayesian forecasting software and clinical expertise, to prescribers at an Australian hospital. A retrospective audit of intravenous vancomycin therapy ( 48 hours) in adults (≥ 18 years old) was undertaken over a 54‐month period to evaluate attainment of established vancomycin pharmacokinetic harmacodynamic targets (AUC over 24 hours / minimum inhibitory concentration: 400–600) before (36‐month period) and after (18‐month period) Service implementation. Interrupted time series analysis was employed to evaluate monthly measures of the median proportion of therapy spent within the target range. Indices of time to target attainment were also assessed before and after Service implementation. The final cohort comprised 1,142 courses of vancomycin (816 patients) 835 courses (596 patients) and 307 courses (220 patients) administered before and after Service implementation, respectively. Prior to piloting the Service, the median proportion of time in the target range was 40.1% (95% CI, 34.3–46.0%) this increased by 10.4% (95% CI, 1.2–19.6%, P = 0.03) after the Service, and was sustained throughout the post‐Service evaluation period. Post‐Service target attainment at 48–72 hours after initiation of therapy was increased (7.8%, 95% CI, 1.3–14.3%, P = 0.02). The findings of this study provide evidence that a consultative TDM Service can facilitate attainment of vancomycin therapeutic targets however, optimization of the Service may further improve the use of vancomycin.
Publisher: Wiley
Date: 21-03-2011
DOI: 10.1111/J.1440-1630.2010.00888.X
Abstract: Grip strength is useful in clinical practice for the assessment of disease and/or rehabilitation progression. Brief maximal gripping is seldom required in everyday occupations, with repeated or sustained gripping at sub-maximal power more commonly involved. It has been proposed that assessment of both maximal hand-grip force and endurance is utilised. While the suitability of maximal contraction measures has been clearly established, the reliability and validity of other hand-grip indices have not been investigated. This study examined the reliability of various hand-grip indices and their validity in relation to distance walked during the six-minute walk test, a standardised exercise capacity test. Subjects undertook static sub-maximal (50%) and maximal force contraction hand-grip testing from which various indices were derived, and six-minute walk testing from which distance walked was determined. Testing was repeated on three separate occasions for determination of test-retest reliability. Pre- and post-fatigue maximal contraction measurements demonstrated excellent test-retest reliability and validity. Conversely, other hand-grip indices were shown to be unreliable and exhibited no relationship with distance walked and hence concurrent validity could not be established. Based on the results of this study, it is recommended that pre- and post-fatigue maximal contraction may be utilised for the assessment of client ability and progression due to their established validity and test-retest reliability. However, previously proposed measures of fatigue such as endurance (duration of sustained contraction), Strength Decrement Index and work performed (function of endurance and force of contraction) are unreliable and invalid and may have limited use in clinical practice.
Publisher: American Society for Microbiology
Date: 17-02-2021
DOI: 10.1128/AAC.02019-20
Abstract: Fluconazole has been associated with higher mortality compared with the echinocandins in patients treated for invasive candida infections. Underexposure from current fluconazole dosing regimens may contribute to these worse outcomes, so alternative dosing strategies require study.
Publisher: Wiley
Date: 27-02-2019
DOI: 10.1111/BCP.13873
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2023
DOI: 10.1097/FTD.0000000000001057
Abstract: The authors present the case of a 34-year-old male patient who underwent therapeutic plasma exchange (TPE) for amyopathic dermatomyositis. Immunosuppression resulted in Aspergillus lentulus pulmonary infection , requiring treatment with super bioavailable-itraconazole. Therapeutic itraconazole concentrations were attained after 2 weeks of treatment after dose adjustments. Interestingly, a substantial reduction in plasma itraconazole concentration was observed during TPE, which was attributed to an insufficient delay between the dosing of itraconazole and TPE initiation. Furthermore, there was an increase in plasma concentration post-TPE, which presumably reflects the redistribution of itraconazole from peripheral compartments back into plasma. This was confirmed by s ling of the TPE plasmapheresate, which revealed that changes in plasma concentration overestimated itraconazole clearance. These findings highlight that the pharmacokinetics of itraconazole are altered during TPE, which should be considered when timing drug administration and obtaining plasma concentrations.
Publisher: American Society for Microbiology
Date: 29-06-2022
DOI: 10.1128/SPECTRUM.02684-21
Abstract: This study examined the pharmacokinetics and viral genomic data from a prospective cohort of kidney transplant recipients undergoing valganciclovir prophylaxis for cytomegalovirus (CMV) prevention. We showed for the first time using high-throughput sequencing the detection of ganciclovir resistance mutations in breakthrough CMV infection during subtherapeutic plasma ganciclovir as indicated by the pharmacokinetic parameter daily area under the curve (AUC 24 ).
Publisher: Wiley
Date: 15-04-2021
DOI: 10.1111/BCP.14844
Abstract: Accurate documentation of medication administration time is imperative for many therapeutic decisions, including dosing of intravenous antimicrobials. The objectives were to determine (1) the discrepancy between actual and documented administration times for antimicrobial infusions and (2) whether day of the week, time of day, nurse‐to‐patient ratio and drug impacted accuracy of documented administration times. Patient and dosing data were collected (June–August 2019) for 55 in‐patients receiving antimicrobial infusions. “Documented” and “actual” administration times ( n = 660) extracted from electronic medication management systems and smart infusion pumps, respectively, were compared. Influence of the day (weekday/weekend), time of day (day/evening/night), nurse‐to‐patient ratio (high 1:1/low 1:5) and drug were examined. Monte Carlo simulation was used to predict the impact on dose adjustments for vancomycin using the observed administration time discrepancies compared to the actual administration time. The median discrepancy between actual and documented administration times was 16 min (range, 2–293 min), with discrepancies greater than 60 minutes in 7.7% of administrations. Overall, discrepancies (median [range]) were similar on weekends (17 [2–293] min) and weekdays (16 [2–188] min), and for high (16 [2–157] min) and low nurse‐to‐patient ratio wards (16 [2–293] min). Discrepancies were smallest for night administrations ( P .05), and antimicrobials with shorter half‐lives ( P .0001). The observed discrepancies in vancomycin administration time resulted in a different dose recommendation in 58% of cases (30% higher, 28% lower). Overall, there were discrepancies between actual and documented antimicrobial infusion administration times. For vancomycin, these discrepancies in administration time were predicted to result in inappropriate dose recommendations.
Publisher: OMICS Publishing Group
Date: 2010
DOI: 10.4172/JBB.1000032
Publisher: Wiley
Date: 25-10-2023
DOI: 10.1002/JCPH.2363
Publisher: Springer Science and Business Media LLC
Date: 07-02-2020
Publisher: SAGE Publications
Date: 11-10-2023
Publisher: Oxford University Press (OUP)
Date: 28-04-2023
Abstract: Therapeutic drug monitoring (TDM) of aminoglycosides and vancomycin is used to prevent oto- and nephrotoxicity in neonates. Analytical and nonanalytical factors potentially influence dosing recommendations. This study aimed to determine the impact of analytical variation (imprecision and bias) and nonanalytical factors (accuracy of drug administration time, use of non-trough concentrations, biological variation, and dosing errors) on neonatal antimicrobial dosing recommendations. Published population pharmacokinetic models and the Australasian Neonatal Medicines Formulary were used to simulate antimicrobial concentration–time profiles in a virtual neonate population. Laboratory quality assurance data were used to quantify analytical variation in antimicrobial measurement methods used in clinical practice. Guideline-informed dosing recommendations based on drug concentrations were applied to compare the impact of analytical variation and nonanalytical factors on antimicrobial dosing. Analytical variation caused differences in subsequent guideline-informed dosing recommendations in 9.3−12.1% (amikacin), 16.2−19.0% (tobramycin), 12.2−45.8% (gentamicin), and 9.6−19.5% (vancomycin) of neonates. For vancomycin, inaccuracies in drug administration time (45.6%), use of non-trough concentrations (44.7%), within-subject biological variation (38.2%), and dosing errors (27.5%) were predicted to result in more dosing discrepancies than analytical variation (12.5%). Using current analytical performance specifications, tolerated dosing discrepancies would be up to 14.8% (aminoglycosides) and 23.7% (vancomycin). Although analytical variation can influence neonatal antimicrobial dosing recommendations, nonanalytical factors are more influential. These result in substantial variation in subsequent dosing of antimicrobials, risking inadvertent under- or overexposure. Harmonization of measurement methods and improved patient management systems may reduce the impact of analytical and nonanalytical factors on neonatal antimicrobial dosing.
Publisher: Wiley
Date: 29-01-2013
DOI: 10.1111/HDI.12021
Publisher: Springer Science and Business Media LLC
Date: 23-06-2023
Publisher: Springer Science and Business Media LLC
Date: 16-02-2016
DOI: 10.1007/S40262-015-0363-2
Abstract: Anorexia can affect up to 90 % of people with advanced cancer. It is a complex symptom associated with changes in taste, lack of hunger at mealtimes and lack of food enjoyment. Associated weight loss is part of the physical decline that occurs as cancer worsens. Weight loss can also occur from cachexia, the increased metabolism of energy due to raised inflammatory cytokines, liver metastases and other factors seen in several advanced cancers. Independent of anorexia, although frequently associated (where it is referred to as the cachexia-anorexia syndrome), it accounts for a significant amount of morbidity and deaths in people with cancer. In particular, quality of life for the patient and the family is significantly affected with this syndrome as it causes anxiety and distress. Therefore, it is important that research into therapies is undertaken, particularly focusing on an understanding of the pharmacokinetic properties of compounds in this cachexic population. Cannabinoids are one such group of therapies that have received a large amount of media focus recently. However, there appears to be a lack on rigorous pharmacokinetic data of these complex and varied compounds in the cachexic population. Similarly, there is a lack of pharmacokinetic data in any population group for the non- tetrahydrocannabinol (THC) and cannabidiol (CBD) cannabinoids (often due to the lack of analytical standards for quantification). This review will thus examine the pharmacokinetics of major cannabinoids i.e. THC and CBD in a cancer population. Overall, based on the current literature, evidence for the use of cannabinoids for the treatment of cancer-related cachexia-anorexia syndrome remains equivocal. A high-quality, rigorous, phase I/II study to elicit pharmacokinetic dose-concentration and concentration-response data, with a clinically acceptable mode of delivery to reduce intrapatient variability and enable more consistent bioavailability is needed in this population.
No related grants have been discovered for Stephanie Reuter Lange.