ORCID Profile
0000-0001-9996-4886
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: Wiley
Date: 17-03-2014
DOI: 10.1111/BCPT.12213
Abstract: Using a modelling approach, this study aimed to (i) examine whether the pharmacodynamics of the analgesic and antihyperalgesic effects of morphine differ (ii) investigate the influence of demographic, pain sensitivity and genetic (OPRM1) variables on between-subject variability of morphine pharmacokinetics and pharmacodynamics in human experimental pain models. The study was a randomized, double-blind, 5-arm, cross-over, placebo-controlled study. The psychophysical cutaneous pain tests, electrical pain tolerance (EPTo) and secondary hyperalgesia areas (2HA) were studied in 28 healthy in iduals (15 males). The subjects were chosen based on a previous trial where 100 subjects rated (VAS) their pain during a heat injury (47°C, 7 min., 12.5 cm(2) ). The 33% lowest- and highest pain-sensitive subjects were offered participation in the present study. A two-compartment linear model with allometric scaling for weight provided the best description of the plasma concentration-time profile of morphine. Changes in the EPTo and 2HA responses with time during the placebo treatment were best described by a linear model and a quadratic model, respectively. The model discrimination process showed clear evidence for adding between-occasion variability (BOV) on baseline and the placebo slope for EPTo and 2HA, respectively. The sensitivity covariate was significant on baseline EPTo values and genetics as a covariate on the placebo slope for 2HA. The analgesic and antihyperalgesic effects of morphine were pharmacologically distinct as the models had different effect site equilibration half-lives and different covariate effects. Morphine had negligible effect on 2HA, but significant effect on EPTo.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1093/BJA/AEP269
Abstract: CNS 7056 is an esterase-metabolized benzodiazepine sedative currently under development. Its short duration of action would suggest a clinical role similar to midazolam or propofol. The effect of a range of doses of CNS 7056, midazolam, and propofol on depth of sedation, the respiratory system, and the cardiovascular system was studied in chronically instrumented sheep (n=5 or 6). The low, medium, and high doses of CNS 7056, midazolam, and propofol were 0.37, 0.74, and 1.47 mg kg(-1) 0.05, 0.1, and 0.2 mg kg(-1) and 1, 2, and 4 mg kg(-1), respectively. CNS 7056 produced substantial sedation with rapid onset and offset for all doses, with duration rather than depth of sedation increasing with the dose. The lower doses of midazolam had minimal sedative effect increasing the dose produced variable but longer term sedation. Sedation from propofol was comparable with that of CNS 7056 for the medium and high doses only. The high doses produced approximately 20 min of sedation. All three drugs produced dose-dependent respiratory (e.g. reductions in arterial oxygen tension) and cardiovascular depression (e.g. reductions in mean arterial pressure). For CNS 7056, midazolam, and propofol, the magnitude of the cardiovascular and respiratory depression was proportional to the depth of sedation achieved for any given drug or dose. For all three drugs, the respiratory and cardiovascular depression was not of sufficient magnitude to endanger the animals. CNS 7056 is a powerful and short-acting anaesthetic in sheep with respiratory and cardiovascular effects consistent with its sedative/anaesthetic qualities.
Publisher: Wiley
Date: 2014
DOI: 10.1038/PSP.2013.71
Publisher: Informa UK Limited
Date: 03-2020
DOI: 10.2147/DDDT.S239704
Publisher: Auckland University of Technology (AUT) Library
Date: 04-05-2016
DOI: 10.24135/TEACHERSWORK.V12I2.181
Abstract: Innovative Learning Environments (ILE) with their origins in OECD literature, propose to revolutionise Education as we know it. ILEs draw on a large body of literature: constructivist learning theory distributed leadership personalised 21st century learning blended learning (digital) and, future focused Education. Despite an increasing body of research in the area, there appears to be confusion around the concept of ILEs in Aotearoa/New Zealand Schools. This article reports on survey research with 126 questionnaire respondents. These principals and teachers, drawn from a random s le of New Zealand schools, commented on the implications of ILEs for teaching and learning in their contexts. This article explores the theoretical framework that educators apply to this concept. Four themes emerged from the responses: lack of clarity the significance of material spaces pedagogical implications and, the politics around ILEs. The authors pose the question: are ILEs just another neoliberal ambush on Education or opportunity to innovate the fundamentals of schooling?
Publisher: Wiley
Date: 15-02-2019
Publisher: Wiley
Date: 22-04-2015
DOI: 10.1111/BCP.12553
Publisher: Wiley
Date: 23-08-2016
DOI: 10.1111/PAN.12995
Abstract: Physiologically-based pharmacokinetic (PBPK) models represent drug kinetics in one or more 'real' organs (and hence require submodels of organs/tissues) and they describe 'whole-body' kinetics by joining together submodels with drug transport by blood flow as dictated by anatomy. They attempt to reproduce 'measureable' physiological and/or pharmacokinetic processes rather than more abstract rate constants and volumes. PBPK models may be built using a 'bottom-up' approach, where parameters are chosen from first principles, literature, or in vitro data as opposed to a 'top-down' approach, where all parameters are estimated from data. The basic principles of PBPK models are described, focusing on the equations for three in idual organs: a single flow-limited compartment describing distribution only, a membrane-limited compartment describing distribution, and a single flow-limited compartment with elimination. These organ models are linked to make a basic three-compartment physiological model of the whole body. PBPK models are particularly suited to scaling kinetics across body size (e.g., adult to neonate) and species (e.g., animal to first-in-man) as physiology and pharmacology can be represented by independent parameters. Maturation models can be incorporated as for compartmental models. PBPK models are now available in commercial software packages, and are perhaps now more accessible than ever. Alternatively, even complex PBPK models can be represented in generic differential equation-solving software using the simple principles described here. The relative ease of constructing the code for PBPK models belies the most difficult aspect of their implementation-collecting, collating, and justifying the data used to parameterize the model.
Publisher: Wiley
Date: 09-2012
DOI: 10.1038/PSP.2012.4
Publisher: SAGE Publications
Date: 05-06-2018
Abstract: Atenolol lactation information is limited, and controversy exists over the safety of its use during breastfeeding. In this study, important parameters including milk-to-plasma ratio, ratio of infant plasma to maternal plasma, infant daily dosage, and relative infant dose were investigated. The findings from this study add information to existing data about atenolol transfer in human milk. This may help guide health professionals in decision making regarding the safety of beta blockers used by mothers during breastfeeding. The aims of the study were to quantify concentrations of atenolol in human plasma and milk, to evaluate atenolol pharmacokinetics in lactating women, and to investigate subsequent infant exposure to atenolol via mother’s milk. In this prospective, longitudinal observational study, participants were lactating mothers ( N = 3), 1 to 4 months postpartum, who had been taking atenolol for therapeutic reasons, and one 4-month-old breastfed infant. Eight milk s les were collected over 24 hr at different time points, together with a single blood s le from each lactating mother and the infant, and quantified using a new sensitive liquid chromatography mass spectrometry method developed for this study. Peak milk concentrations of atenolol were observed in the women at 4 hr (T max ) after oral administration. The dose-normalized maximum concentrations (C max ) of all patients were similar. The mean milk-to-plasma ratio of the patients who were taking 25 to 100 mg of atenolol was 8.57%. In the mother–infant pair study, the ratio (%) of infant plasma drug concentration to maternal plasma drug concentration observed (18.87%) was similar to the relative infant dose estimated (18.20%). The relative infant dose values (13.96%-18.20%) for all patients were within 10% to 25% of maternal dosage. Atenolol use during breastfeeding should be undertaken with some precaution. If clinically indicated, an alternate beta blocker may be preferred.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.EJPS.2016.02.021
Abstract: Polymorphisms in the opioid receptor genes may affect the pharmacodynamics (PD) of oxycodone and be part of the reason behind the ersity in clinical response. The aim of the analysis was to model the exposure-response profile of oxycodone for three different pain variables and search for genetic covariates. Model simulations were used to predict how population and effect-size impact the power to detect clinical significant SNPs. The population pharmacokinetic-pharmacodynamic (PKPD) model of oral single-dosed oxycodone was based on pooled data from three published studies in healthy volunteers. Pain tolerance data from muscle pressure (n=36), visceral pressure (n=54) and skin pinch (n=34) were included. Genetic associations with 18 opioid-receptor SNPs were explored using a stepwise covariate approach. Model simulations were performed using the estimated model parameters. None of the selected SNPs were associated with analgesic response of oxycodone at P<0.001. Baseline response in muscle cuff pressure was associated with OPRK1 rs7016778 and rs7824175 (P 50% for similar population sizes) or large populations (n>200 for a 20% response difference) are necessary to identify clinical significant SNP effects due to high population variability. A population PKPD model has been developed for oral oxycodone using three different pain variables to explore impact of genetic covariates and study design. None of the selected polymorphisms were significantly associated with analgesic response of oxycodone, but an association of baseline response in muscle cuff pressure with two OPRK1 SNPs was identified.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2019
DOI: 10.1007/S13318-018-0519-1
Abstract: SUBA-itraconazole and Sporanox are two oral formulations of itraconazole. Drug-drug interactions with omeprazole have been previously reported however, mechanistic understanding of the pharmacological and physiological interactions of omeprazole with orally administered itraconazole within a population modeling paradigm is lacking. The objective of this analysis was to mechanistically describe and quantify the effect of omeprazole on the pharmacokinetics of itraconazole and its major metabolite, hydroxyitraconazole from the SUBA itraconazole and Sporanox formulations. An in vitro-in vivo (IVIV) pharmacokinetic model of itraconazole and hydroxyitraconazole was developed including data from an omeprazole interaction study with SUBA itraconazole. Meta-models of gastric pH for healthy subjects and subjects receiving omeprazole were integrated into the IVIV model to capture omeprazole-mediated gastric pH changes on itraconazole dissolution and absorption. Omeprazole influenced the kinetics of itraconazole through altering the dissolution and absorption due to the pH-dependent solubility of itraconazole, inhibition of efflux transporters, and inhibiting the metabolism of itraconazole and hydroxyitraconazole. The model-predicted population effects of omeprazole on itraconazole from SUBA-itraconazole were to increase the area under the concentration-time curve (AUC Unlike SUBA itraconazole, which requires basic pH for itraconazole release, the omeprazole-induced pH-mediated reduction in Sporanox dissolution overrides any increased exposure from the drug-drug interaction at hepatic metabolizing enzymes or efflux transporters. The model presented here is the most complete quantitative description of the pharmacokinetics of itraconazole and hydroxyitraconazole currently available.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 14-10-2016
Abstract: Leflunomide's active metabolite teriflunomide inhibits dihydro-oroate dehydrogenase, an enzyme essential to proliferation of T lymphocytes. As teriflunomide must reach the target site to have this effect, this study assessed the distribution of teriflunomide into T lymphocytes, as intracellular concentrations may be a superior response biomarker to plasma concentrations. CD3 MicroBeads (Miltenyi Biotec, Bergisch Gladbach, Germany) were used to extract CD3
Publisher: Springer Science and Business Media LLC
Date: 28-01-2021
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.EJPS.2014.10.003
Abstract: The aim of this study was to develop population pharmacokinetic-pharmacodynamic models for morphine in experimental pain induced by skin heat and muscle pressure, and to evaluate the experimental pain models with regard to assessment of morphine pharmacodynamics. In a randomised, double-blind, placebo-controlled, crossover study, 39 healthy volunteers received an oral dose of 30mg morphine hydrochloride or placebo. Non-linear mixed effects modelling was used to describe the plasma concentrations of morphine and metabolites, and the analgesic effect of morphine on experimental pain in skin and muscle. Baseline pain metrics varied between in iduals and occasions, and were described with interin idual and interoccasion variability. Placebo-response did not change with time. For both pain metrics, morphine effect was proportional to baseline pain and was described with a linear model with interin idual variability on drug effect slope and linked to an effect compartment for muscle pressure. The models indicate that a steady-state morphine concentration of 21ng/ml causes 33% and 0.84% increases in stimulus intensity from baseline for muscle pressure and skin heat, respectively. The population pharmacokinetic-pharmacodynamic models developed in this study indicate that mechanical stimulation of muscle is a more clinically relevant pain stimulus for the assessment of morphine pharmacodynamics than thermal stimulation of skin.
Publisher: Wiley
Date: 04-2013
DOI: 10.1038/PSP.2013.14
Publisher: Informa UK Limited
Date: 10-2018
DOI: 10.2147/DDDT.S184053
Publisher: Springer Science and Business Media LLC
Date: 06-09-2019
Publisher: MDPI AG
Date: 28-02-2022
DOI: 10.3390/PHARMACEUTICS14030542
Abstract: The age-related loss of circulating estrogen that occurs during the menopausal transition manifests itself through a variety of symptoms including vasomotor (hot flushes and night sweats), genito-urinary syndrome (vaginal dryness and urinary symptoms), sexual dysfunction, mood, and sleep disturbance that often last longer than a decade. Furthermore, reductions in estrogen level increase the risks of chronic complications such as osteoporosis, cardiovascular disease, and cognitive decline among others, thereby affecting the quality of life of women. Although oral estrogens are the most widely used therapy for menopausal symptoms, they suffer from poor bioavailability, and there are concerns over their safety, creating a significant concern to consumers. Mucoadhesive buccal films are an innovative dosage form that offers several advantages including avoidance of the first-pass metabolism, fast onset of action, and importantly, improved patient acceptance. In the current work, we developed mucoadhesive estradiol film for hormonal replacement therapy using film-forming polymers. Two approaches, namely, co-solvency and nano-emulsion were evaluated to increase solubility and hence incorporate estradiol, a poorly water-soluble drug, into a formulation made from the hydrophilic polymer/s. The films were characterised for their mechanical and physicochemical properties. In-vitro release study showed that about 80% of the drug was released within 6 min from films prepared by the nano-emulsion approach, whereas it took about 10.5 min to get similar drug release from films prepared by the co-solvency approach. The ex-vivo permeation result indicates that about 15% of the drug permeated across the porcine buccal mucosa in the first 10 h from films prepared by the nano-emulsion approach, while permeation across porcine buccal mucosa was only observed at around 24 h from films prepared by the co-solvency method. The nano-emulsion films were evaluated for in vivo performance using a convolution technique using R software. The predicted Cmax and Tmax were found to be 740.74 ng mL−1 and 7 min, respectively, which were higher than previously reported in vivo concentration from oral tablets. The results demonstrated that mucoadhesive film of estradiol based on the nano-emulsion approach could be a promising platform for the delivery of estradiol through the buccal mucosa for the treatment of menopausal symptoms.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2018
DOI: 10.1007/S10928-017-9555-8
Abstract: The aim of this study was to develop a population in vitro-in vivo pharmacokinetic model that simultaneously describe the absorption and accumulation kinetics of itraconazole (ICZ) and hydroxy-itraconazole (HICZ) in healthy subjects. The model integrated meta-models of gastrointestinal pH and gastrointestinal transit time and in vitro dissolution models of ICZ with the absorption and disposition kinetics of ICZ and HICZ. Mean concentration intravenous data, and single- and multi-dose oral data were used for model development. Model development was conducted in NONMEM in a stepwise manner. First, a model of intravenous data (systemic kinetics) was established and then extended to include the oral data. The latter was then extended to establish the in vitro-in vivo pharmacokinetic model. The systemic disposition of ICZ was best described by a 3-compartment model with oral absorption described by 4-transit compartments and HICZ distribution by a 1-compartment model. ICZ clearance was best described using a mixed inhibition model that allowed HICZ concentrations to inhibit the clearance of parent drug. HICZ clearance was described by Michaelis-Menten elimination kinetics. An in vitro-in vivo model was successfully established for both formulations. The presented model was able to describe ICZ and HICZ plasma concentrations over a wide range of oral and intravenous doses and allowed the exploration of complexities associated with the non-linear ICZ and HICZ kinetics. The model may provide insight into the variability in exposure of ICZ with respect to relating in vivo dissolution characteristics with in vivo disposition kinetics.
Publisher: Wiley
Date: 27-07-2021
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.EJPB.2016.11.034
Abstract: This article reviews the major physiological and physicochemical principles of the effect of food and gastrointestinal (GI) pH on the absorption and bioavailability of oral drugs, and the various absorption models that are used to describe redict oral drug absorption. The rate and extent of oral drug absorption is determined by a complex interaction between a drug's physicochemical properties, GI physiologic factors, and the nature of the formulation administered. GI pH is an important factor that can markedly affect oral drug absorption and bioavailability as it may have significant influence on drug dissolution & solubility, drug release, drug stability, and intestinal permeability. Different regions of the GI tract have different drug absorptive properties. Thus, the transit time in each GI region and its variability between subjects may contribute to the variability in the rate and/or extent of drug absorption. Food-drug interactions can result in delayed, decreased, increased, and sometimes un-altered drug absorption. Food effects on oral absorption can be achieved by direct and indirect mechanisms. Various models have been proposed to describe oral absorption ranging from empirical models to the more sophisticated "mechanism-based" models. Through understanding of the physicochemical and physiological rate-limiting factors affecting oral absorption, modellers can implement simplified population-based modelling approaches that are less complex than whole-body physiologically-based models but still capture the essential elements in a physiological way and hence will be more suited for population modelling of large clinical data sets. It will also help formulation scientists to better predict formulation performance and to develop formulations that maximize oral bioavailability.
Publisher: Wiley
Date: 08-12-2010
DOI: 10.1111/J.1742-7843.2010.00649.X
Abstract: Pharmacokinetic harmacodynamic (PK/PD) modelling can be used to characterize the relationship between dose regimen of opioids, plasma concentration and effect of opioids, which in turn can lead to more rational treatment regimens of pain. The aim of this study was to investigate the concentration-effect relationship for transdermal buprenorphine and fentanyl in experimentally induced pain. Twenty-two healthy volunteers were randomized to receive transdermal patches with fentanyl (25 μg/hr, 72 hr), buprenorphine (20 μg/hr, 144 hr) or placebo. The experimental pain tests were pressure at the tibial bone, cutaneous thermal stimulation, cold pressor test (conditioning stimulus (3 ± 0.3°C cold water), nerve growth factor-induced muscle soreness and intradermal capsaicin-induced hyperalgesia and allodynia. Experiments were carried out at baseline, 24, 48, 72 and 144 hr after application of patches. Time-course of placebo was described first and was afterwards added to the description of the time-courses of buprenorphine and fentanyl. This was either described by zero (no drug effect), linear or E(max) model concentration-effect relationships. Time-dependent changes in pain measures in the placebo arm were described by linear or quadratic functions. The time-course of fentanyl and buprenorphine plasma concentrations was complex but could be represented by cubic spline interpolation in the models. Buprenorphine significantly attenuated bone-associated pain, heat pain, nerve growth factor-induced soreness and cold pressor pain. Fentanyl significantly attenuated cold pressor pain for the administered dose regimens. Although the PK/PD relationship for both drugs could be described with similar models, tissue-differentiated analgesic effects between buprenorphine and fentanyl was shown.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2016
DOI: 10.1208/S12248-016-9952-8
Abstract: This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) pH in the different GI segments characterize the effect of food on the values and variability in these parameters and present quantitative meta-models of distributions of GI pH to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, GI pH under fed and fasted conditions. The GI tract was categorized into the following 10 distinct regions: stomach (proximal, mid-distal), duodenum (proximal, mid-distal), jejunum and ileum (proximal, mid, and distal small intestine), and colon (ascending, transverse, and descending colon). Meta-analysis used the "metafor" package of the R language. The time course of postprandial stomach pH was modeled using NONMEM. Food significantly influenced the estimated meta-mean stomach and duodenal pH but had no significant influence on small intestinal and colonic pH. The time course of postprandial pH was described using an exponential model. Increased meal caloric content increased the extent and duration of postprandial gastric pH buffering. The different parts of the small intestine had significantly different pH. Colonic pH was significantly different for descending but not for ascending and transverse colon. Knowledge of GI pH is important for the formulation design of the pH-dependent dosage forms and in understanding the dissolution and absorption of orally administered drugs. The meta-models of GI pH may also be used as part of semi-physiological pharmacokinetic models to characterize the effect of GI pH on the in vivo drug release and pharmacokinetics.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2016
DOI: 10.1208/S12248-016-9953-7
Abstract: This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) transit times of non-disintegrating single-unit ("tablet") and multiple-unit ("pellets/multi-unit tablet") solid dosage forms, characterize the effect of food on the values and variability in these parameters and present quantitative meta-models of the distributions of GI transit times in the respective GI regions to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, gastric, small intestinal and colonic transit times under fed and fasted conditions. Meta-analysis used the "metafor" package of the R language. Meta-models of GI transit were assumed to be log-normally distributed between the studied populations. Twenty-nine studies including 125 reported means and standard deviations were used in the meta-analysis. Caloric content of administered food increased variability and delayed the gastric transit of both pellets and tablets. Conversely, food caloric content reduced the variability but had no significant influence on the mean small intestinal transit time (SITT). Food had no significant effect on the transit time through the colon. The transit of pellets through the colon was significantly slower than that of single-unit tablets which is most likely related to their smaller size. GI transit times may influence the dissolution and absorption of oral drugs. The meta-models of GI transit times may be used as part of semi-physiological absorption models to characterize the influence of transit time on the dissolution, absorption and in vivo pharmacokinetic profiles of oral drugs.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Wiley
Date: 28-10-2019
DOI: 10.1111/BCPT.13330
Abstract: Oral controlled-release formulations are playing an ever-increasing role in opioid therapy however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic-pharmacodynamics of two controlled-release tablet formulations and a liquid formulation of oxycodone in healthy, opioid-naïve volunteers, which can serve as a reference for future patient studies. A semi-double-blinded, three-way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled-release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post-dose. Oxycodone pharmacokinetics was best described by a two-compartment model with first-order absorption. The controlled-release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (k
Publisher: MDPI AG
Date: 21-09-2021
DOI: 10.3390/PHARMACEUTICS13091524
Abstract: Three-dimensional (3D) printing is among the rapidly evolving technologies with applications in many sectors. The pharmaceutical industry is no exception, and the approval of the first 3D-printed tablet (Spiratam®) marked a revolution in the field. Several studies reported the fabrication of different dosage forms using a range of 3D printing techniques. Thermosensitive drugs compose a considerable segment of available medications in the market requiring strict temperature control during processing to ensure their efficacy and safety. Heating involved in some of the 3D printing technologies raises concerns regarding the feasibility of the techniques for printing thermolabile drugs. Studies reported that semi-solid extrusion (SSE) is the commonly used printing technique to fabricate thermosensitive drugs. Digital light processing (DLP), binder jetting (BJ), and stereolithography (SLA) can also be used for the fabrication of thermosensitive drugs as they do not involve heating elements. Nonetheless, degradation of some drugs by light source used in the techniques was reported. Interestingly, fused deposition modelling (FDM) coupled with filling techniques offered protection against thermal degradation. Concepts such as selection of low melting point polymers, adjustment of printing parameters, and coupling of more than one printing technique were exploited in printing thermosensitive drugs. This systematic review presents challenges, 3DP procedures, and future directions of 3D printing of thermo-sensitive formulations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2020
DOI: 10.1097/ANA.0000000000000596
Abstract: The clinical use of vasoactive drugs aims to improve hemodynamic variables and thereby maintain or restore adequate perfusion and oxygenation in accordance with metabolic demands. A main focus in the management of patients with brain pathology during surgery and neurointensive care is restoring and/or maintaining adequate cerebral perfusion pressure in order to ensure cerebral blood flow in accordance with metabolic demands. One commonly used clinical strategy is the administration of vasoactive drugs aiming to increase mean arterial blood pressure and thereby cerebral perfusion pressure. Here, we first describe the anatomic and physiological basis for the cerebrovascular effects of vasopressor agents. Next, we review the pharmacodynamics of commonly used vasopressors under normal circumstances and in the presence of head injury. We further discuss the role of blood-brain barrier disruption and microvascular dysfunction with regard to the effects of the reviewed vasopressor agents.
Publisher: Wiley
Date: 27-02-2019
DOI: 10.1111/BCP.13873
Publisher: Informa UK Limited
Date: 12-03-2017
Publisher: Wiley
Date: 28-10-2015
DOI: 10.1111/BCP.12760
Publisher: American Society for Microbiology
Date: 03-2017
DOI: 10.1128/AAC.02401-16
Abstract: The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion ( P 0.01) and then backward deletion ( P 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability ( F ), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.
Publisher: Wiley
Date: 10-2015
DOI: 10.1002/PSP4.12036
Publisher: Hindawi Limited
Date: 08-07-2014
DOI: 10.1111/JCPT.12189
Abstract: A common polymorphism (C1858T) in the gene that encodes the protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with altered T-cell responses and increased susceptibility to rheumatoid arthritis (RA) and other autoimmune diseases. Teriflunomide, the active metabolite of leflunomide, reduces T-cell responses through inhibition of tyrosine kinase p56LCK. We examined a potential association between PTPN22 genotype and response or toxicity to leflunomide in Caucasian RA patients taking leflunomide in combination with other disease-modifying antirheumatic drugs (DMARDs). Patients enrolled in the Royal Adelaide Hospital RA inception cohort and taking leflunomide were eligible for inclusion. Participants were followed for 12 months after leflunomide initiation or until either another DMARD was added or leflunomide was ceased. Clinical response according to change in 28-joint Disease Activity Score (DAS28) and cessation due to toxicity were assessed. A total of 94 participants were included in the study, 75 of whom carried the CC genotype, 18 the CT, whereas one in idual carried the TT genotype. Over the first 12 months of leflunomide treatment, there was no statistically significant relationship between carrying the T allele and change in DAS28 (-0·84 vs. -1·15, P = 0·446) nor with cessation of leflunomide treatment due to side effects (P = 0·433). These results indicate that PTPN22 C1858T genotype has no effect on response or toxicity outcomes in leflunomide-treated RA patients. This is the first study to evaluate the biologically plausible hypothesis that PTPN22 genotype might be a predictor of response/toxicity to leflunomide therapy. Despite this, PTPN22 genotype was not associated with leflunomide response or toxicity in patients with RA.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2012
DOI: 10.1007/S00280-012-1998-4
Abstract: Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor that has demonstrated manageable safety and high response rates in patients with chronic phase (CP) chronic myeloid leukemia (CML). The current analysis evaluated potential bosutinib pharmacokinetic-pharmacodynamic relationships. Bosutinib exposure metrics at steady state were estimated from a previously developed population pharmacokinetic model. Safety and efficacy metrics were from two clinical studies of bosutinib 500 mg/day in patients with CP CML. The analysis included 749 patients (aged 18-91 years mean weight, 75 kg 54% male). An exposure-response relationship was identified for the pooled incidence (but not severity) of diarrhea, with predicted probability ranging from 0.575 to 0.797 for the lowest and highest area under the curve bins, respectively a weak relationship was also observed for the incidence of rash (predicted probability, 0.216-0.419). There was no evidence of an exposure-response relationship for nausea, vomiting, neutropenia, thrombocytopenia, or elevated alanine and aspartate aminotransferases. Exposure-response relationships were observed in patients with newly diagnosed CP CML for complete cytogenetic response at 1 year (predicted probability, 0.476-0.650), major molecular response at 1 year (0.238-0.497), and cumulative complete hematologic response (CHR) at 1 year (0.605-0.763). Patients with previously treated CP CML showed no exposure-response relationship for major cytogenetic response at 24 weeks (0.320) for CHR, higher bosutinib exposure was associated with a lower probability of response (0.926-0.743). The absence of exposure-response relationships for some safety and efficacy metrics may reflect bosutinib exposure metrics that exceeded the half-maximal inhibitory values and achieved a maximum effect.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.IJPHARM.2022.122324
Abstract: Despite being an effective therapy for menopausal symptoms, the use of oral estrogen is associated with low bioavailability and serious adverse effects of venous thromboembolism. In idualized therapy has been recommended to maximize benefits and curb the adverse effects, but much has not been done in developing formulations that offer flexibility to personalize therapy. In the present study, we employed an innovative 3D printing technology to design and develop bi-layered estradiol film with different infill patterns with an aim of improving bioavailability and facilitating personalized treatment. Hydroxypropyl cellulose (HPC-H) based formulation exhibited suitable rheological properties and was used as a feedstock to fabricate estradiol films with different infill patterns namely honeycomb, rectangular and plain. The back layer was prepared from a hydroxyethyl cellulose-based formulation. The resulting films were subsequently characterized in terms of their physicochemical, mechanical, environmental impact, and release characteristics among others. Films with a plain infill pattern exhibited significantly higher % elongation break and tensile strength. The in vitro drug release study revealed the fastest drug release profile for rectangular infill (96 % within 4 h) and the slowest drug release was observed for the plain infill pattern (∼35 % within 4 h), highlighting the effect of the infill pattern on release kinetics. Films with honeycomb infill patterns were selected for further characterization based on mechanical and in vitro release properties. No interaction between components of the formulation was observed and the absence of crystallinity in the final product was confirmed by Differential Scanning Calorimetry (DSC) and X-Ray Powder Diffraction analyses (XRD). The force of adhesiveness for the film was 0.13 ± 0.03 N. The predicted AUC 0-4 h, C
Publisher: American Society for Microbiology
Date: 09-2015
DOI: 10.1128/AAC.00973-15
Abstract: Itraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and s le size estimation, which are important aspects of clinical trial design of bioequivalence studies.
Publisher: Bentham Science Publishers Ltd.
Date: 03-2020
DOI: 10.2174/1389200221666200502015203
Abstract: p75ECD-Fc is a recombinant human protein that has recently been developed as a novel therapy for Alzheimer’s disease. Current studies showed that it is able to alleviate Alzheimer’s disease pathologies in animal models of dementia. Thus, knowledge about the pharmacokinetic behavior and tissue distribution of this novel protein is crucial in order to better understand its pharmacodynamics and more importantly for its clinical development. The aim of this study is to characterize the pharmacokinetics of p75ECD-Fc after single intravenous and subcutaneous injection of 3mg/kg in Sprague Dawley rats. We calculated the bioavailability of the SC route and studied the distribution of that protein in different tissues, cerebrospinal fluid and urine using ELISA and immunofluorescence techniques. In-vitro stability of the drug was also assessed. Data obtained were analyzed with Non-compartmental pharmacokinetic method using R. Results showed that the bioavailability of SC route was 66.15%. Half-life time was 7.5 ± 1.7 and 6.2 ± 2.4 days for IV and SC injection, respectively. Tissue distribution of p75ECD-Fc was modest with the ability to penetrate the blood brain barrier. It showed high in vitro stability in human plasma. These acceptable pharmacokinetic properties of p75ECD-Fc present it as a potential candidate for clinical development for the treatment of Alzheimer’s disease.
Publisher: Springer Science and Business Media LLC
Date: 03-04-2021
Publisher: American Physiological Society
Date: 03-2015
DOI: 10.1152/JAPPLPHYSIOL.00944.2014
Abstract: In underwater ing, decompression schedules are based on compartmental models of nitrogen and helium tissue kinetics. However, these models are not based on direct measurements of nitrogen and helium kinetics. In isoflurane-anesthetized sheep, nitrogen and helium kinetics in the hind limb (n = 5) and brain (n = 5) were determined during helium-oxygen breathing and after return to nitrogen-oxygen breathing. Nitrogen and helium concentrations in arterial, femoral vein, and sagittal sinus blood s les were determined using headspace gas chromatography, and venous blood flows were monitored continuously using ultrasonic Doppler. The experiment was repeated at different states of hind limb blood flow and cerebral blood flow. Using arterial blood gas concentrations and blood flows as input, parameters and model selection criteria of various compartmental models of hind limb and brain were estimated by fitting to the observed venous gas concentrations. In both the hind limb and brain, nitrogen and helium kinetics were best fit by models with multiexponential kinetics. In the brain, there were no differences in nitrogen and helium kinetics. Hind limb models fit separately to the two gases indicated that nitrogen kinetics were slightly faster than helium, but models with the same kinetics for both gases fit the data well. In the hind limb and brain, the blood:tissue exchange of nitrogen is similar to that of helium. On the basis of these results, it is inappropriate to assign substantially different time constants for nitrogen and helium in all compartments in decompression algorithms.
Publisher: Informa UK Limited
Date: 12-01-2021
Publisher: Springer Science and Business Media LLC
Date: 15-02-2022
Publisher: Springer Science and Business Media LLC
Date: 27-01-2020
DOI: 10.1208/S12248-020-0414-Y
Abstract: Exposure-response (ER) modeling for fixed-dose combinations (FDC) has previously been found to have an inflated false positive rate (FP), i.e., observing a significant effect of FDC components when no true effect exists. Longitudinal exposure-response (LER) analysis utilizes the time course of the data and is valid for several clinical endpoints for FDCs. The aim of the study was to investigate if LER is applicable for the validation of FDCs by demonstrating the contribution of each component to the overall effect without inflation of FP rates. FP and FN rates associated with ER and LER analysis were investigated using stochastic simulation and estimation. Four hundred thirty-two scenarios with varying numbers of patients, duration, s ling frequency, dose distribution, design, and drug activity were analyzed using a range of linear, log-linear, and non-linear models to asses FP and FN rates. Lastly, the impact of the clinical trial parameters was investigated. LER analyses provided well-controlled FP rates of the expected 5% or less however, in low information clinical trials consisting of 30 patients, 4 s les, and 20 days, LER analyses lead to inflated FN rates. Parameter investigation showed that when the clinical trial includes sufficient patients, duration, s les, and an appropriate trial design, the FN rates are in general below the expected 5% for LER analysis. Based on the results, LER analysis can be used for the validation of FDCs and fixed ratio drug combinations. The method constitutes a new avenue for providing evidence that demonstrates the contribution of each component to the overall clinical effect.
No related grants have been discovered for Richard Upton.