Kathryn Ball (1), Maud Beneton (1), Emilie Leroux (1), Marylore Chenel (1)
(1) Clinical Pharmacokinetics and Pharmacometrics Department, Institut de Recherches Internationales Servier, Suresnes, France, (2) Nonclinical Pharmacokinetics and Biopharmaceutical Research Department, Technologie Servier, Orleans, France
Objectives: A PBPK model for an orally administered Servier compound (S1) was built in order to predict its PK in Chinese patients, both in the presence and absence of food, to aid the design of the first in man study in the Chinese population. The predictions were then compared to the observed data from the clinical study.
Methods: A PBPK model was built for S1 in the Simcyp software, using in vitro data including solubility at a range of pH values, Caco-2 permeability, plasma protein binding, and intrinsic clearance in hepatocytes. The model was first qualified using in vivo plasma concentration-time data from a dose-finding study in Caucasians. A Chinese population exists within Simcyp, which takes into account differences in demographic characteristics and enzyme abundance [1]. The model was then used to simulate the therapeutic dose in Chinese patients, and compared with the data from European Caucasian patients. The model was then used to simulate the PK in Chinese patients in the presence and absence of food, in order to anticipate a food effect [2]. The data from a subsequent clinical study in Chinese patients was used to evaluate the goodness of these predictions.
Results: The predicted geometric mean AUCss of S1 in Chinese patients (fasted) was 1.5-fold of that in European Caucasian patients (fasted), compared to the observed Chinese-to-European AUCss ratio of 1.4-fold. The food effect simulation in the Chinese population using the PBPK model predicted an S1 AUCss in the fed state which was 1.0-fold of the AUCss in the fasted state. This was confirmed by the observed data, which also gave a 1.0-fold AUCss ratio (fed vs fasted).
Conclusions: The AUCss of the Chinese patients was well predicted by the PBPK model. Demographic differences, such as the lower abundance of CYP3A4 in Chinese patients versus Caucasians, and the smaller liver size of Chinese versus Caucasians, result in a lower hepatic clearance in Chinese patients. Demographic differences which affect absorption, and which were not taken into account in the model, may affect the fraction absorbed of S1. Nevertheless, a negligible food effect was predicted in the Chinese population using the PBPK model, and this was found to be in very good agreement with the observed data, which also showed a negligible food effect.
References:
[1] Barter ZE, Tucker GT, Rowland-Yeo K. Differences in cytochrome P450-mediated pharmacokinetics between Chinese and Caucasian populations predicted by mechanistic physiologically based pharmacokinetic modelling. Clin Pharmacokinet. 2013. 52 : p. 1085-1100.
[2] Jamei M, Turner D, Yang J, Neuhoff S, et al. Population-based mechanistic prediction of oral drug absorption. AAPS J, 2009. 11 : p. 225-237.
Reference: PAGE 25 (2016) Abstr 5952 [www.page-meeting.org/?abstract=5952]
Poster: Drug/Disease modeling - Absorption & PBPK