Prediction of drug exposure in hepatic impairment: a comparison between minimal physiologically based pharmacokinetic (mPBPK) and whole body PBPK models

Abstract

Aim: The objective of this study was to develop a minimal physiologically based pharmacokinetic (mPBPK) model to predict area under the curve (AUC) and maximum plasma concentration (C_max) of drugs in subjects with varying degrees of hepatic impairment and compare this mPBPK model with the whole body PBPK model.

Methods: Hepatic impairment classification system, which is based on Child-Pugh score was used. In this mPBPK model, 4 physiological parameters [portal and renal blood flow, glomerular filtration rate (GFR), and liver size] and 2 biochemical parameters (albumin and bilirubin) were used. Total number of drugs analyzed in this study was 52, and the predicted C_max and AUC values were compared with dedicated clinical trials. Out of 52 drugs, the predictive performance of mPBPK was compared with the whole body PBPK model for 27 drugs, and the remaining 25 drugs were used to further test the robustness of the mPBPK model.

Results: The results of the study indicated that the predictive performance of the mPBPK model was comparable with the whole body PBPK model, both in terms of C_max and AUC. For 52 drugs, there were 120 data points for AUC (37, 47, and 36 for mild, moderate, and severe hepatic impairment, respectively), and from mPBPK model, 92%, 94%, and 89% data points were within 0.5–2-fold prediction error, respectively.

Conclusions: Overall, the results of the study indicated that the proposed mPBPK model, in its predictive performance, is as robust and accurate as whole body PBPK model.

Keywords

Hepatic impairment / physiological parameters / minimal physiologically based pharmacokinetic / whole body physiologically based pharmacokinetic / area under the curve / maximum plasma concentration

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