Ruijuan Xu1, Weihong Ge2, Qing Jiang3. 1. Department of Pharmacy, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Zhongshan Road 321, Nanjing, 210008, China. jean0129@163.com. 2. Department of Pharmacy, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Zhongshan Road 321, Nanjing, 210008, China. 6221230@sina.com. 3. Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Zhongshan Road 321, Nanjing, 210008, China. qingj@nju.edu.cn.
Abstract
PURPOSE: Rivaroxaban is a direct oral anticoagulant with a large inter-individual variability. The present study is to develop a physiologically based pharmacokinetic (PBPK) model to predict several scenarios in clinical practice. METHODS: A whole-body PBPK model for rivaroxaban, which is metabolized by the cytochrome P450 (CYP) 3A4/5, 2J2 pathways and excreted via kidneys, was developed to predict the pharmacokinetics at different doses in healthy subjects and patients with hepatic or renal dysfunction. Hepatic clearance and drug-drug interactions (DDI) were estimated by in vitro in vivo extrapolation (IVIVE) based on parameters obtained from in vitro experiments. To validate the model, observed concentrations were compared with predicted concentrations, and the impact of special scenarios was investigated. RESULTS: The PBPK model successfully predicted the pharmacokinetics for healthy subjects and patients as well as DDIs. Sensitivity analysis shows that age, renal, and hepatic clearance are important factors affecting rivaroxaban pharmacokinetics. The predicted fold increase of rivaroxaban AUC values when combined administered with the inhibitors such as ketoconazole, ritonavir, and clarithromycin were 2.3, 2.2, and 1.3, respectively. When DDIs and hepatic dysfunction coexist, the fold increase of rivaroxaban exposure would increase significantly compared with one factor alone. CONCLUSIONS: Our study using PBPK modeling provided a reasonable approach to evaluate exposure levels in special patients under special scenarios. Although further clinical study or real-life experience would certainly merit the current work, the modeling work so far would at least suggest caution of using rivaroxaban in complicated clinical settings.
PURPOSE:Rivaroxaban is a direct oral anticoagulant with a large inter-individual variability. The present study is to develop a physiologically based pharmacokinetic (PBPK) model to predict several scenarios in clinical practice. METHODS: A whole-body PBPK model for rivaroxaban, which is metabolized by the cytochrome P450 (CYP) 3A4/5, 2J2 pathways and excreted via kidneys, was developed to predict the pharmacokinetics at different doses in healthy subjects and patients with hepatic or renal dysfunction. Hepatic clearance and drug-drug interactions (DDI) were estimated by in vitro in vivo extrapolation (IVIVE) based on parameters obtained from in vitro experiments. To validate the model, observed concentrations were compared with predicted concentrations, and the impact of special scenarios was investigated. RESULTS: The PBPK model successfully predicted the pharmacokinetics for healthy subjects and patients as well as DDIs. Sensitivity analysis shows that age, renal, and hepatic clearance are important factors affecting rivaroxaban pharmacokinetics. The predicted fold increase of rivaroxaban AUC values when combined administered with the inhibitors such as ketoconazole, ritonavir, and clarithromycin were 2.3, 2.2, and 1.3, respectively. When DDIs and hepatic dysfunction coexist, the fold increase of rivaroxaban exposure would increase significantly compared with one factor alone. CONCLUSIONS: Our study using PBPK modeling provided a reasonable approach to evaluate exposure levels in special patients under special scenarios. Although further clinical study or real-life experience would certainly merit the current work, the modeling work so far would at least suggest caution of using rivaroxaban in complicated clinical settings.
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