Comparative assessment of In Vitro-In Vivo extrapolation methods used for predicting hepatic metabolic clearance of drugs

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Journal of Pharmaceutical Sciences (Impact Factor: 2.59). 11/2012; 101(11):4308-26. DOI: 10.1002/jps.23288
Source: PubMed


The purpose of this study was to perform a comparative analysis of various in vitro--in vivo extrapolation (IVIVE) methods used for predicting hepatic metabolic clearance (CL) of drugs on the basis of intrinsic CL data determined in microsomes. Five IVIVE methods were evaluated: the conventional and conventional bias-corrected methods using the unbound fraction in plasma (fup), the Berezhkovskiy method in which the fup is adjusted for drug ionization, the Poulin et al. method using the unbound fraction in liver (fuliver), and the direct scaling method, which does not consider any binding corrections. We investigated the effects of the following scenarios on the prediction of CL: the use of preclinical or human datasets, the extent of plasma protein binding, the magnitude of CL in vivo, and the extent of drug disposition based on biopharmaceutics drug disposition classification system (BDDCS) categorization. A large and diverse dataset of 139 compounds was collected, including those from the literature and in house from Genentech. The results of this study confirm that the Poulin et al. method is robust and showed the greatest accuracy as compared with the other IVIVE methods in the majority of prediction scenarios studied here. The difference across the prediction methods is most pronounced for (a) albumin-bound drugs, (b) highly bound drugs, and (c) low CL drugs. Predictions of CL showed relevant interspecies differences for BDDCS class 2 compounds; the direct scaling method showed the greatest predictivity for these compounds, particularly for a reduced dataset in rat that have unexpectedly high CL in vivo. This result is a reflection of the direct scaling method's natural tendency to overpredict the true metabolic CL. Overall, this study should facilitate the use of IVIVE correlation methods in physiologically based pharmacokinetics (PBPK) model. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:43084326, 2012

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Available from: Sami Haddad, May 06, 2014
    • "Equation (3) represents the intrinsic in vitro clearance CL int,LM , Equation (4) scales CL int,LM to the full liver, while Equation (5) assumes the direct scaling approach as representative of in vivo hepatic clearance (Poulin et al., 2012), although this approach may overestimate the in vivo clearance in case of extensive plasma protein binding. In these equations, the following scaling factors were used: 34 mg/g microsomal proteins per g liver, 0.71 mL/min/g liver for hepatic clearance (Q H ) and a relative liver mass of 2.6 g liver/kg bodyweight (Lipscomb and Poet, 2008). "
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