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Application of physiologically based pharmacokinetic modeling to the prediction of drug-drug and drug-disease interactions for rivaroxaban

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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.

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Author information

Authors and Affiliations

  1. Department of Pharmacy, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Zhongshan Road 321, Nanjing, 210008, China

    Ruijuan Xu & Weihong Ge

  2. Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Zhongshan Road 321, Nanjing, 210008, China

    Qing Jiang

Authors
  1. Ruijuan Xu
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  2. Weihong Ge
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  3. Qing Jiang
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Contributions

Ruijuan Xu developed the model and performed the validation. All the authors contributed the discussion of results. Ruijuan Xu wrote the first draft. All the authors reviewed the data and approved the final version of submission.

Corresponding authors

Correspondence to Ruijuan Xu, Weihong Ge or Qing Jiang.

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Conflict of interest

This work was supported by the Key Research and Development program of Jiangsu Province of China (No. BE2016608). We thank Professor Jin Yang from China Pharmaceutical University for providing SimCYP® software (Version 14.0).

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Cite this article

Xu, R., Ge, W. & Jiang, Q. Application of physiologically based pharmacokinetic modeling to the prediction of drug-drug and drug-disease interactions for rivaroxaban. Eur J Clin Pharmacol 74, 755–765 (2018). https://doi.org/10.1007/s00228-018-2430-8

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  • DOI: https://doi.org/10.1007/s00228-018-2430-8

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