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Effect of CYP3A4, CYP3A5, ABCB1 Gene Polymorphisms on Rivaroxaban Pharmacokinetics in Patients Undergoing Total Hip and Knee Replacement Surgery

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Abstract

Introduction

Population ageing in developed countries will inevitably increase the need for knee and hip replacement surgery. Over the years, direct oral anticoagulants, such as rivaroxaban, have been widely used for thromboprophylaxis in patients undergoing knee and hip replacement surgery. The study of pharmacogenetic characteristics of rivaroxaban is important for enhancing the effectiveness and safety of rivaroxaban thromboprophylaxis.

Aim

Evaluation of CYP3A4, CYP3A5 and ABCB1 gene polymorphisms influence on rivaroxaban pharmacokinetics and prothrombin time dynamics in patients undergoing total hip and knee replacement surgery.

Methods

The study included 78 patients undergoing total hip and knee replacement surgery. The patients received 10 mg of rivaroxaban once a day. Genotyping of polymorphisms ABCB1 rs1045642, ABCB1 rs4148738, CYP3A4 rs35599367 and CYP3A5 rs776746 was performed. Peak steady-state and trough steady-state rivaroxaban concentrations were determined. Prothrombin time was also evaluated.

Results

The study revealed the following haplotypes: (1) ABCB1 rs1045642—CYP3A4 rs35599367 and (2) ABCB1 rs4148738—CYP3A4 rs35599367. The analysis of the peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes revealed no significant differences. However, there was a statistically significant average correlation between peak steady-state rivaroxaban concentration and prothrombin time (r = 0.421; r2 = 0.178; p < 0.001).

Conclusion

No significant difference was identified in peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes. The revealed statistically significant average correlation between the prothrombin time and peak steady-state rivaroxaban concentration is important in clinical practice for assessing the anticoagulant activity of rivaroxaban.

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Acknowledgements

This study was supported by Russian Science Foundation, project 16-15-00227 “Conducting fundamental scientific research and exploratory research on priority thematic research areas”. We would also like to thank all who participated in this study from Sechenov University’s Clinic of Traumatology, Orthopaedics and Joint Pathology, Department of Clinical Pharmacology and Propedeutics of Internal Diseases of Sechenov University and the R&D Center of Russian Medical Academy for Continuous Professional Education under the Ministry of Health of Russia.

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Authors and Affiliations

  1. Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation

    Dmitry Sychev

  2. Department of Clinical Pharmacology and Propaedeutics of Internal Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow, 119991, Russian Federation

    Radik Minnigulov & Irina Yudina

  3. Personalized Medicine Department, Research Center, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation

    Pavel Bochkov

  4. Department of Molecular Biological Research, Research Center, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation

    Kristina Ryzhikova

  5. Department of Traumatology, Orthopedics and Disaster Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow, 119991, Russian Federation

    Aleksey Lychagin

  6. Department of General Medical Practice, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya St., Moscow, 119991, Russian Federation

    Tatyana Morozova

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  1. Dmitry Sychev
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Correspondence to Radik Minnigulov.

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Sychev, D., Minnigulov, R., Bochkov, P. et al. Effect of CYP3A4, CYP3A5, ABCB1 Gene Polymorphisms on Rivaroxaban Pharmacokinetics in Patients Undergoing Total Hip and Knee Replacement Surgery. High Blood Press Cardiovasc Prev 26, 413–420 (2019). https://doi.org/10.1007/s40292-019-00342-4

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  • DOI: https://doi.org/10.1007/s40292-019-00342-4

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