Predictive performance of next generation physiologically based kinetic (PBK)-model predictions in rats based on in vitro and in silico input data

Author:

Punt Ans1,Louisse Jochem1,Pinckaers Nicole1,Fabian Eric2,van Ravenzwaay Bennard2

Affiliation:

1. Wageningen Food Safety Research, Akkermaalsbos 2, 6708 WB Wageningen, the Netherlands

2. BASF SE, Experimental Toxicology and Ecology, Carl Bosch Straße 38, 67056, Ludwigshafen, Germany

Abstract

Abstract The goal of the present study was to assess the predictive performance of a minimal generic rat physiologically based kinetic (PBK) model based on in vitro and in silico input data to predict peak plasma concentrations (Cmax) upon single oral dosing. To this purpose, a dataset was generated of 3960 Cmax predictions for 44 compounds, applying different combinations of in vitro and in silico approaches for chemical parameterization, and comparison of the predictions to reported in vivo data. Best performance was obtained when i) the hepatic clearance was parameterized based on in vitro measured intrinsic clearance values, ii) the method of Rodgers and Rowland for calculating partition coefficients, and iii) in silico calculated fraction unbound plasma and Papp values (the latter especially for very lipophilic compounds). Based on these input data, the median Cmax of 32 compounds could be predicted within 10-fold of the observed Cmax, with 21 out of these 32 compounds being predicted within 5-fold, and 8 compounds within 2-fold. Overestimations of more than 10-fold were observed for 12 compounds, whereas no underestimations of more than 10-fold occurred. Median Cmax predictions were frequently found to be within 10-fold of the observed Cmax when the scaled unbound hepatic intrinsic clearance (Clint,u) was either higher than 20 L/h or lower than 1 L/h. Similar findings were obtained with a test set of five in-house BASF compounds. Overall, this study provides relevant insights in the predictive performance of a minimal PBK model based on in vitro and in silico input data.

Publisher

Oxford University Press (OUP)

Subject

Toxicology

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