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Methods for Predicting In Vivo Pharmacokinetics Using Data from In Vitro Assays

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Strategies for optimising in vivo predictions from in vitro data on metabolic stability and CYP inhibition are discussed. Potential pitfalls and areas of inaccuracy are highlighted together with recommendations for best practice. The use of both hepatic microsomes and isolated hepatocytes for the assessment of metabolic stability is discussed in terms of scaling from the in vitro system up to whole liver. The importance of integrating metabolic stability data together with other drug pharmacokinetic characteristics (e.g., protein binding and red blood cell uptake) as well as blood flow are presented within the context of different liver models. The assessment of CYP inhibition potential requires in vitro data on the inhibitor potency either in the form of Ki (for reversible inhibition) or KI and kinact (for time-dependent inhibition). The integration of these in vitro parameters together with other pharmacokinetic information is essential for the in vivo prediction. While a qualitative assessment may be made from the I/Ki ratio, a number of additional victim drug and enzymerelated parameters are required for quantitative prediction. Of particular importance is the parameter fmCYP (the fraction of the metabolic clearance of the victim drug that is catalyzed by the enzyme subject to the inhibition). Impact of other victim drug properties (e.g., fractional importance of the intestine) and enzyme properties (e.g., kdeg for time-dependent inhibition) on the drug-drug interaction prediction is discussed. In addition, mechanisms by which false negatives and false positives may result from in vitro strategies are summarized. Finally perspectives for future application and improvements in these predictions strategies are outlined.

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Keywords: Clearance prediction; assessment of CYP inhibition potential; in vitro-in vivo extrapolation; quantitative prediction of drug-drug interactions

Document Type: Research Article

Publication date: November 1, 2008

More about this publication?
  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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