Physiologically Based Pharmacokinetic Modeling of Fimasartan, Amlodipine, and Hydrochlorothiazide for the Investigation of Drug–Drug Interaction Potentials

• DOI: 10.1007/s11095-018-2511-5
• Publication Date: 2018-10-15T13:07:00Z
• Authors: Su-jin Rhee; Hyun A. Lee; Soyoung Lee; Eunwoo Kim; Inseung Jeon; Im-Sook Song; Kyung-Sang Yu
• Keywords: Biphenyl Compounds; Tetrazoles; Models, Biological; 3. Good health; 03 medical and health sciences; Hydrochlorothiazide; Pyrimidines; 0302 clinical medicine; Humans; Computer Simulation; Drug Interactions; Amlodipine; Antihypertensive Agents; Software

To build a physiologically based pharmacokinetic (PBPK) model for fimasartan, amlodipine, and hydrochlorothiazide, and to investigate the drug-drug interaction (DDI) potentials.The PBPK model of each drug was developed using Simcyp software (Version 15.0), based on the information obtained from literature sources and in vitro studies. The predictive performance of the model was assessed by comparing the predicted PK profiles and parameters with the observed data collected from healthy subjects after multiple oral doses of fimasartan, amlodipine, and hydrochlorothiazide. The DDI potentials after co-administration of three drugs were simulated using the final model.The predicted-to-observed ratios of all the pharmacokinetic parameters met the acceptance criterion. The PBPK model predicted no significant DDI when fimasartan was co-administered with amlodipine or hydrochlorothiazide, which is consistent with the observed clinical data. In the simulation of DDI at steady-state after co-administration of three drugs, the model predicted that fimasartan exposure would be increased by ~24.5%, while no changes were expected for the exposures of amlodipine and hydrochlorothiazide.The developed PBPK model adequately predicted the pharmacokinetics of fimasartan, amlodipine, and hydrochlorothiazide, suggesting that the model can be used to further investigate the DDI potential of each drug.