Ibrahim Ince (1), Jan-Frederik Schlender (1), Katrin Coboeken (1), Katrin Schnizler (2), Stefan Willman (3) Rolf Burghaus (1)
(1) Bayer AG, Systems Pharmacology & Medicine, Leverkusen, Germany, (2) Bayer AG, Pharmacometrics Study Mgmt. & Quality, Leverkusen, Germany, (3) Bayer AG, Clinical Pharmacometrics, Wuppertal, Germany
Objectives: Physiologically-based pharmacokinetic (PBPK) modeling is considered a valuable tool for predicting pharmacokinetic changes of drugs in different populations to subsequently guide in-vivo pharmacokinetic trials. The goal of this study is to extrapolate physiologically-based pharmacokinetic models for small molecule drugs in healthy Caucasian adults to healthy Japanese adults. Predictive performance of this bridging approach is verified by predicting the pharmacokinetics of small molecule drugs acetaminophen, ciprofloxacin, midazolam, and theophylline in healthy Japanese adults and comparing to clinically observed data.
Methods: A systematic literature search was carried out to identify and collect study data on Japanese anatomical, physiological, and functional parameters to establish a PBPK population model for healthy Japanese individuals. The database was implemented in the Open Systems Pharmacology (OSP) Suite [1]. Small molecule drugs for verification of the predictive performance of the PBPK model were selected according to the availability of published data. First, PBPK models for the small molecule drugs acetaminophen, ciprofloxacin, midazolam, and theophylline were created in Caucasian adults. Subsequently, these population PBPK models were applied to predict the PK of the four compounds in Japanese adults, where the activity and variability of relevant enzymatic processes (e.g. CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1, CYP3A4, SULT1A1, and UGT1A1) was implemented. Bridging the PBPK models from Caucasian to Japanese adults accounted for the differences in anthropometric, anatomical and physiological parameters (e.g. body weight, body height, organ volumes, blood flow rates and tissue composition). Prediction results were evaluated by comparison with experimentally observed literature data and with comparison of observed versus predicted PK measures.
Results: PBPK population models for healthy Japanese were established in the OSP Suite. PK for acetaminophen, ciprofloxacin, midazolam, and theophylline in Caucasian and Japanese adults was extracted from literature. First, population PBPK models in Caucasian adults including the relevant enzymatic processes were established and successfully predicted the PK of acetaminophen, ciprofloxacin, midazolam, and theophylline. Second, the PBPK models for these small molecule drugs were extrapolated and correctly predicted the PK in the Japanese adult population. As a result, for Caucasian and Japanese, more than 90% of the predicted mean plasma concentrations and PK measures for all drugs fell within the 2-fold error range of the reported values.
Conclusions: We successfully developed four Japanese population PBPK models and systematically evaluated the predictive performance of these extrapolated PBPK models from healthy Caucasian to Japanese adults using acetaminophen, ciprofloxacin, midazolam, and theophylline as exemplary small molecule drugs. Ultimately, this bridging approach could be applied to investigate in silico the PK of other small molecule drugs and help design clinical trials in Japanese adults.
References:
[1] http://www.open-systems-pharmacology.org/
Reference: PAGE 27 (2018) Abstr 8706 [www.page-meeting.org/?abstract=8706]
Poster: Drug/Disease Modelling - Absorption & PBPK