Application of PBPK modeling to predict human intestinal metabolism of CYP3A substrates - an evaluation and case study using GastroPlus.

F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, Non-Clinical Safety, Basel, Switzerland.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences (Impact Factor: 2.61). 06/2012; 47(2):375-86. DOI: 10.1016/j.ejps.2012.06.013
Source: PubMed

ABSTRACT First pass metabolism in the intestinal mucosa is a determinant of oral bioavailability of CYP3A substrates and so the prediction of intestinal availability (Fg) of potential drug candidates is important. Although intestinal metabolism can be modeled in commercial physiologically based pharmacokinetic (PBPK) software tools, a thorough evaluation of prediction performance is lacking. The current study evaluates the accuracy and precision of GastroPlus Fg predictions for 20 CYP3A substrates using in vitro and in silico input data for metabolic clearance and membrane permeation, and illustrates a potential impact of intestinal metabolism modeling on decision making in a drug Research and Development project. This analysis supports that CYP3A mediated metabolic clearance measured in human liver microsomes can be used to predict gut wall metabolism. Using values scaled from in vitro cell permeability as input for effective jejunal permeability resulted in good Fg prediction accuracy (no significant bias and ∼95% of predictions within 2 fold from in vivo estimated Fg), whereas simulations with in silico predicted permeability tended to overestimate gut metabolism (40% of Fg predictions under predicted more than 2 fold) ±2 fold range as an estimate of imprecision in metabolic clearance and permeability inputs propagated to >5 and <2 fold ranges of predicted Fg for compounds with <30% and >75% in vivo Fg, respectively, suggesting lower precision of predictions for high extraction compounds. Furthermore, parameter sensitivity analysis suggests that limitations in solubility or dissolution may either decrease Fg by preventing saturation of metabolism or increase Fg by shifting the site of absorption towards the colon where expression of CYP3A is low. The case example illustrates how, when accounting for the associated uncertainty in predicted pharmacokinetics and linking to predictive models for efficacy, PBPK modeling of intestinally metabolized compounds can support decision making in drug Research and Development.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: To facilitate accurate predictions of oral drug disposition, mechanistic absorption models require optimal parameterization. Furthermore, parameters should maintain a biological basis to establish confidence in model predictions. This study will serve to calculate an optimal parameter value for small intestinal water volume (SIWV) using a model-based approach. To evaluate physiologic fidelity, derived volume estimates will be compared to experimentally-based SIWV determinations. A compartmental absorption and transit (CAT) model, created in Matlab-Simulink®, was integrated with a whole-body PBPK model, developed in PK-SIM 5.2®, to provide predictions of systemic drug disposition. SIWV within the CAT model was varied between 52.5mL and 420mL. Simulations incorporating specific SIWV values were compared to pharmacokinetic data from compounds exhibiting solubility induced non-proportional changes in absorption using absolute average fold-error. Correspondingly, data pertaining to oral administration of acyclovir and chlorothiazide were utilized to derive estimates of SIWV. At 400mg, a SIWV of 116mL provided the best estimates of acyclovir plasma concentrations. A similar SIWV was found to best depict the urinary excretion pattern of chlorothiazide at a dose of 100mg. In comparison, experimentally-based estimates of SIWV within adults denote a central tendency between 86 and 167mL. The derived SIWV (116mL) represents the optimal parameter value within the context of the developed CAT model. This result demonstrates the biological basis of the widely utilized CAT model as in vivo SIWV determinations correspond with model-based estimates. Copyright © 2014 Elsevier B.V. All rights reserved.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 11/2014; 67C:55-64. · 2.61 Impact Factor
  • Source
    Dataset: Guohaifang
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pharmacokinetics (PK) refers to the time course of drug concentrations in the body and since knowledge of PK aids understanding of drug efficacy and safety, numerous PK studies are performed in animals and humans during the drug development process. In vitro to in vivo extrapolation (IVIVE) and physiologically-based pharmacokinetic (PBPK) modeling are tools that integrate data from various in silico, in vitro and in vivo sources to deliver mechanistic quantitative simulations of in vivo PK. PBPK models are used to predict human PK and to evaluate the effects of intrinsic factors such as organ dysfunction, age and genetics as well as extrinsic factors such as co-administered drugs. In recent years the use of PBPK within the industry has greatly increased. However insufficient data on how the abundance of metabolic enzymes and membrane transporters vary in different human patient populations and in different species has been a limitation. A major advance is therefore expected through reliable quantification of the abundance of these proteins in tissues. This review describes the role of PBPK modelling in drug discovery and development, outlines the assumptions involved in integrating protein abundance data, and describes the advances made and expected in determining abundance of relevant proteins through mass spectrometric techniques. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    PROTEOMICS - CLINICAL APPLICATIONS 02/2015; · 1.81 Impact Factor


Available from
May 21, 2014