74
221.75
3.00
85

Publication History View all

  • [Show abstract] [Hide abstract]
    ABSTRACT: Valproic acid is an anti-convulscant drug that is widely used in the treatment of different types of epilepsy and since its introduction the clinical use has increased rapidly both as a sole agent and in combination therapies. The mechanism of action has been linked to blockade of voltage-dependent sodium channels and potentiation of GABAergic transmission. The most widely used route of administration of valproic acid is oral, although it can also be given intravenously and rectally and its pharmacokinetics has been studied extensively. The aim of this work was to develop a physiologically based pharmacokinetic model for plasma and tissue/organ prediction in children and adults following intravenous and oral dosing of valproic acid. The plasma/tissue concentration profile will be used for clinical trial simulation in Dravet syndrome, a rare form of epilepsy in children where the combination of valproic acid, stiripentol and clobazam has shown remarkable results. A physiologically based pharmacokinetic model was developed with compartments for gut lumen, enterocyte, gut tissue, systemic blood, kidney, liver, brain, spleen, muscle and rest of body. System and drug specific parameters for the model were obtained from the literature from in vitro and in vivo experiments. The model was initially developed for adults and scaled to children using age-dependent changes in anatomical and physiological parameters and ontogeny functions for enzyme maturation assuming the same elimination pathways in adults and children. The results from the model validation showed satisfactory prediction of plasma concentration both in terms of mean prediction and variability in children and adults following intravenous and oral dosing especially after single doses. The model also adequately predicts clearance in children. Due to limited distribution of valproic acid into tissues, the concentration in plasma is about 8-9 times higher than tissues/organs. The model could help to improve clinical outcome in the treatment of Dravet syndrome through dose optimisation.
    European Journal of Pharmaceutical Sciences 10/2014; 63:45–52.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To develop and evaluate a tool for the qualitative prediction of human oral bioavailability (Fhuman) from animal oral bioavailability (Fanimal) data employing ROC analysis and to identify the optimal thresholds for such predictions. A dataset of 184 compounds with known Fhuman and Fanimal in at least one species (mouse, rat, dog and non-human primates (NHP)) was employed. A binary classification model for Fhuman was built by setting a threshold for high/low Fhuman at 50%. The thresholds for high/low Fanimal were varied from 0 to 100 to generate the ROC curves. Optimal thresholds were derived from 'cost analysis' and the outcomes with respect to false negative and false positive predictions were analyzed against the BDDCS class distributions. We successfully built ROC curves for the combined dataset and per individual species. Optimal Fanimal thresholds were found to be 67% (mouse), 22% (rat), 58% (dog), 35% (NHP) and 47% (combined dataset). No significant trends were observed when sub-categorizing the outcomes by the BDDCS. Fanimal can predict high/low Fhuman with adequate sensitivity and specificity. This methodology and associated thresholds can be employed as part of decisions related to planning necessary studies during development of new drug candidates and lead selection.
    Pharmaceutical Research 09/2013;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pharmacokinetic models range from being entirely "exploratory" and empirical, to semi-mechanistic and ultimately complex physiologically based pharmacokinetic (PBPK) models. This choice is conditional on the modelling purpose as well as the amount and quality of the available data. The main advantage of PBPK models is that they can be used to extrapolate outside the studied population and experimental conditions. The trade-off for this advantage is a complex system of differential equations with a considerable number of model parameters. When these parameters cannot be informed from in vitro or in silico experiments they are usually optimised with respect to observed clinical data. Parameter estimation in complex models is a challenging task associated with many methodological issues which are discussed here with specific recommendations. Concepts such as structural and practical identifiability are described with regards to PBPK modelling and the value of experimental design and sensitivity analyses is sketched out. Parameter estimation approaches are discussed, while we also highlight the importance of not neglecting the covariance structure between model parameters and the uncertainty and population variability that is associated with them. Finally the possibility of using model order reduction techniques and minimal semi-mechanistic models that retain the physiological-mechanistic nature only in the parts of the model which are relevant to the desired modelling purpose is emphasized. Careful attention to all the above issues allows us to successfully integrate information from in vitro or in silico experiments together with information deriving from observed clinical data and develop mechanistically sound models with clinical relevance.
    British Journal of Clinical Pharmacology 09/2013;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An increasing prevalence of morbid obesity has led to dramatic increases in the number of bariatric surgeries performed. Altered gastrointestinal physiology following surgery can be associated with modified oral drug bioavailability (Foral). In the absence of clinical data, an indication of changes to Foral via systems pharmacology models would be of value in adjusting dose levels after surgery. A previously developed virtual "post-bariatric surgery" population was evaluated through mimicking clinical investigations on cyclosporine and atorvastatin after bariatric surgery. Cyclosporine simulations displayed a reduced fraction absorbed through gut wall (fa) and Foral after surgery, consistent with reported observations. Simulated atorvastatin Foral postsurgery was broadly reflective of observed data with indications of counteracting interplay between reduced fa and an increased fraction escaping gut wall metabolism (FG). Inability to fully recover observed atorvastatin exposure after biliopancreatic diversion with duodenal switch highlights the current gap regarding the knowledge of associated biological changes.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e47; doi:10.1038/psp.2013.23; advance online publication 12 June 2013.
    CPT: pharmacometrics & systems pharmacology. 06/2013; 2:e47.
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: To apply physiologically-based pharmacokinetic (PBPK) modeling to investigate the consequences of reduction in activity of hepatic and intestinal uptake and efflux transporters by cyclosporine and its metabolite AM1. METHODS: Inhibitory potencies of cyclosporine and AM1 against OATP1B1, OATP1B3 and OATP2B1 were investigated in HEK293 cells +/- pre-incubation. Cyclosporine PBPK model implemented in Matlab was used to assess interaction potential (+/- metabolite) against different processes (uptake, efflux and metabolism) in liver and intestine and to predict quantitatively drug-drug interaction with repaglinide. RESULTS: Cyclosporine and AM1 were potent inhibitors of OATP1B1 and OATP1B3, IC(50) ranging from 0.019-0.093 μM following pre-incubation. Cyclosporine PBPK model predicted the highest interaction potential against liver uptake transporters, with a maximal reduction of >70% in OATP1B1 activity; the effect on hepatic efflux and metabolism was minimal. In contrast, 80-97% of intestinal P-gp and CYP3A4 activity was reduced due to the 50-fold higher cyclosporine enterocytic concentrations relative to unbound hepatic inlet. The inclusion of AM1 resulted in a minor increase in the predicted maximal reduction of OATP1B1/1B3 activity. Good predictability of cyclosporine-repaglinide DDI and the impact of dose staggering are illustrated. CONCLUSIONS: This study highlights the application of PBPK modeling for quantitative prediction of transporter-mediated DDIs with concomitant consideration of P450 inhibition.
    Pharmaceutical Research 11/2012;
  • Clinical Pharmacology &#38 Therapeutics 11/2012;
  • [Show abstract] [Hide abstract]
    ABSTRACT: A key parameter in whole-body physiologically based pharmacokinetic models is the tissue-to-plasma water partition coefficient (K(pu) ), which is commonly assumed consistent across all species for all tissues for passively distributing drugs. Many drugs primarily bind to tissue lipids and although considerable tissue lipid concentration data exist in rodents, data on these and K(pu) values in larger animals and humans are sparse to negligible. To test the above assumption, lipid levels were quantified in 13 dog tissues, then compared with the values in rat, and used to predict and compare K(pu) values between these species. For many tissues, including muscle, lipid concentrations were comparable in dog and rat. However, spleen acidic phospholipid levels were sevenfold lower, skin neutral phospholipid threefold lower, and neutral lipids fivefold, 12-fold, and eightfold lower in brain, lung, and spleen, respectively, and fourfold higher in bone in dog than in rat. Such differences resulted in significant predicted K(pu) differences. In contrast, unbound volume of distribution (Vu(ss) ), a global measure of distribution, showed generally good agreement (predictions and observations) between dog and rat for a diverse compound set, indicating tissues with large-predicted K(pu) species differences tend either to contribute to Vu(ss) to a limited extent, and/or occur in opposing directions tending to cancel each other out. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    Journal of Pharmaceutical Sciences 09/2012;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Due to the multi-factorial physiological implications of bariatric surgery, attempts to explain trends in oral bioavailability following bariatric surgery using singular attributes of drugs or simplified categorisations such as the biopharmaceutics classification system have been unsuccessful. So we have attempted to use mechanistic models to assess changes to bioavailability of model drugs. Pharmacokinetic post bariatric surgery models were created for Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch, sleeve gastrectomy and jejunoileal bypass, through altering the 'Advanced Dissolution Absorption and Metabolism' (ADAM) model incorporated into the Simcyp® Simulator. Post to pre surgical simulations were carried out for five drugs with varying characteristics regarding their gut wall metabolism, dissolution and permeability (simvastatin, omeprazole, diclofenac, fluconazole and ciprofloxacin). The trends in oral bioavailability pre to post surgery were found to be dependent on a combination of drug parameters, including solubility, permeability and gastrointestinal metabolism as well as the surgical procedure carried out. In the absence of clinical studies, the ability to project the direction and the magnitude of changes in bioavailability of drug therapy, using evidence-based mechanistic pharmacokinetic in silico models would be of significant value in guiding prescribers to make the necessary adjustments to dosage regimens for an increasing population of patients who are undergoing bariatric surgery.
    The Journal of pharmacy and pharmacology. 07/2012; 64(7):1008-24.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Underprediction of in vivo intrinsic clearance (CL(int)) of unbound drug from human hepatic in vitro systems using physiological extrapolation methodology is accepted as a common outcome. Poulin et al. (2012. J Pharm Sci 101:838-851) recently proposed an approach involving determination of effective fraction unbound in plasma (fu(p)) based on albumin-facilitated hepatic uptake of acidic/neutral drugs which improved prediction accuracy and precision for 25 drugs highly bound to plasma proteins. This approach includes correction of unbound drug according to the ionisation fraction either side of the plasma membrane based on pH difference. Here, we assessed the proposed method using a larger database of predictions of CL(int) for 107 drugs involving hepatocytes (89 drugs) and microsomes (64 drugs). The proposed method was similarly effective in minimising average prediction bias (to within twofold), unlike the conventional fu(p) correction method. However, precision was similar between methods and there was no evidence in the larger database that prediction bias was associated with fu(p). Prediction bias for hepatocytes was clearance dependent by either method, indicating important sources of bias from in vitro methodology. Therefore, to progress beyond empirical correction of bias, there is further need of mechanistic elucidation to improve prediction methodology.
    Journal of Pharmaceutical Sciences 06/2012; 101(8):2645-52.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interindividual variability in activity of uptake transporters is evident in vivo, yet limited data exist in vitro, confounding in vitro-in vivo extrapolation. The uptake kinetics of seven organic anion-transporting polypeptide substrates was investigated over a concentration range in plated cryopreserved human hepatocytes. Active uptake clearance (CL(active, u)), bidirectional passive diffusion (P(diff)), intracellular binding, and metabolism were estimated for bosentan, pitavastatin, pravastatin, repaglinide, rosuvastatin, telmisartan, and valsartan in HU4122 donor using a mechanistic two-compartment model in Matlab. Full uptake kinetics of rosuvastatin and repaglinide were also characterized in two additional donors, whereas for the remaining drugs CL(active, u) was estimated at a single concentration. The unbound affinity constant (K(m, u)) and P(diff) values were consistent across donors, whereas V(max) was on average up to 2.8-fold greater in donor HU4122. Consistency in K(m, u) values allowed extrapolation of single concentration uptake activity data and assessment of interindividual variability in CL(active) across donors. The maximal contribution of active transport to total uptake differed among donors, for example, 85 to 96% and 68 to 87% for rosuvastatin and repaglinide, respectively; however, in all cases the active process was the major contributor. In vitro-in vivo extrapolation indicated a general underprediction of hepatic intrinsic clearance, an average empirical scaling factor of 17.1 was estimated on the basis of seven drugs investigated in three hepatocyte donors, and donor-specific differences in empirical factors are discussed. Uptake K(m, u) and CL(active, u) were on average 4.3- and 7.1-fold lower in human hepatocytes compared with our previously published rat data. A strategy for the use of rat uptake data to facilitate the experimental design in human hepatocytes is discussed.
    Drug metabolism and disposition: the biological fate of chemicals 06/2012; 40(9):1744-56.
Information provided on this web page is aggregated encyclopedic and bibliographical information relating to the named institution. Information provided is not approved by the institution itself. The institution’s logo (and/or other graphical identification, such as a coat of arms) is used only to identify the institution in a nominal way. Under certain jurisdictions it may be property of the institution.