How to handle the delayed or missed dose of rivaroxaban in patients with non-valvular atrial fibrillation: model-informed remedial dosing

ABSTRACT

Background

Rivaroxaban is an oral anticoagulant widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). During long-term anticoagulant therapy, delayed or missed doses are common. This study aimed to explore appropriate remedial dosing regimens for non-adherent rivaroxaban-treated patients.

Methods

Monte Carlo simulation based on a previously established rivaroxaban population pharmacokinetic/pharmacodynamic (PK/PD) model for patients with NVAF was employed to design remedial dosing regimens. The proposed regimens were compared with remedial strategies in the European Heart Rhythm Association (EHRA) guide by assessing deviation time in terms of drug concentration, factor Xa activity, and prothrombin time.

Results

The proposed remedial dosing regimens were dependent on delay duration. The missed dose should be taken immediately when the delay does not exceed 6 h; a half dose is advisable when the delay is between 6 and 20 h. A missed dose should be skipped if less than 4 h remains before the next dose. The proposed regimens resulted in shorter deviation time than that of the EHRA guide.

Conclusion

PK/PD modeling and simulation provide valid evidence on the remedial dosing regimen of rivaroxaban, which could help to minimize the risk of bleeding and thromboembolism.

KEYWORDS:

• Rivaroxaban
• population pharmacokinetics
• pharmacodynamics
• modeling and simulation
• adherence

Acknowledgments

The authors thank Dr. I.G. Girgis from Janssen Pharmaceuticals Research & Development, Raritan, USA for providing details and active discussions on the coding. The authors thank Hai-ni Wen MPharm., and Yun-peng Guo MPharm. from Shanghai Chest Hospital for their critical comments. The authors would also thank Editage (www.editage.cn) for English language editing.

Article highlights

• We recommended to take the missed rivaroxaban dose when no more than 6 h delay; a half dose is recommended after that. When it is closed to next dose, the missed dose should be skipped.

• Age, renal function, body weight and dosing interval do not have a significant effect on remedial dosing regimens.

• Model-informed remedial dosing regimens may provide better solutions than the recommendation by the European Heart Rhythm Association guide.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Author contributions

Xiao-qin Liu: Conceptualization, Methodology, Formal analysis, Writing-original draft, Writing-review & editing, Visualization. Yi-wei Yin: Writing-original draft, Writing-review & editing, Visualization. Chen-yu Wang: Formal analysis, Data curation, Visualization. Zi-ran Li: Formal analysis, Data curation. Xiao Zhu: Writing-review & editing. Zheng Jiao: Conceptualisation, Methodology, Writing-original draft, Writing-review & editing, Supervision, Project administration.

Reviewer disclosures

A reviewer of this manuscript discloses having served in several Advisory Boards for the clinical development of rivaroxaban. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here

Additional information

Funding

This manuscript was not funded.