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: 3.35). 06/2012; 47(2):375-86. DOI: 10.1016/j.ejps.2012.06.013
Source: PubMed


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.

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Available from: Neil Parrott, Apr 26, 2014
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    • "Absorption, distribution and excretion of compounds with poor passive membrane permeability is often significantly affected by active transport. PBPK modeling of such compounds has been limited by insufficient information on protein abundance and the lack of verified methods to translate in vitro measurements of transport to the in vivo situation [115] [116] [123]. This limits the predictive utility of the approach since in vivo data is needed to allow optimization of empirical scaling factors [17]. "
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    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.
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    • "In this case, parameters affecting rate and extent of absorption were solubility, permeability, particle size, intestinal transit times and gastric emptying time. As the most sensitive parameter, permeability was selected to adjust the intestinal absorption model whereas other parameters were kept at default values (Heikkinen et al., 2012). The multiplicative P eff factor was used to modulate P eff in order to fit the absorption phase for the simulated profile and obtain C max and T max values to within 30% of the observed values. "
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