title: Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin.
abstract: Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI usingin silico,in vivoandin vitroderived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the "fit for purpose" application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in Cmaxof caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.
authors.forename: Seok-Ho
authors.initials: SH
authors.lastname: Shin
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.
authors.forename: Jin-Ju
authors.initials: JJ
authors.lastname: Byeon
authors.affiliation: Department of Chemistry and Research Institute for Basic Sciences, Kyung Hee University, Seoul 02453, Korea.
authors.forename: Gwan-Ho
authors.initials: GH
authors.lastname: Lee
authors.affiliation: Advanced Analysis Center, Korea Institute of Science and Technology, Seoul 02792, Korea.
authors.forename: Byung-Yong
authors.initials: BY
authors.lastname: Yu
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.
authors.forename: Young G
authors.initials: YG
authors.lastname: Shin
keywords: Caffeine; Ciprofloxacin; Drug-drug interaction; Physiologically based pharmacokinetics