Optimizing rivaroxaban therapy through therapeutic drug monitoring (TDM): A review article

  • A Made Dea Almas Majoring of Pharmacology, Master Program of Biomedical Science, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Indonesia
  • Juliana Purukan Majoring of Pharmacology, Master Program of Biomedical Science, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Indonesia
  • Widhowati Supardi Majoring of Pharmacology, Master Program of Biomedical Science, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Indonesia
Keywords: Rivaroxaban, pharmacokinetics, pharmacodynamic, anticoagulant, therapeutic drug monitoring

Abstract

Therapeutic drug monitoring (TDM) is a technique used to measure and analyze plasma drug concentrations to optimize dosages for individual patients. The goal is to maintain drug concentration within target ranges to maximize therapeutic effects and prevent side effects. Rivaroxaban, a popular direct oral anticoagulant (DOAC) could cause risks such as drug interactions and bleeding. Therapeutic drug monitoring can help mitigate these risks by ensuring personalized and appropriate dosing for the individual patient. Within 2-4 hr after a dose, rivaroxaban reaches peak concentrations due to its rapid absorption with nearly perfect absorption at a 10 mg dose. Its pharmacodynamic effects are dose-dependent. There are no significant interactions between rivaroxaban and NSAIDs like naproxen or acetylsalicylic acid. Rivaroxaban exhibits potential for clinically significant interactions with drugs that inhibit CYP3A/P-gp pathways or possess antithrombotic properties. Notably, co-administration with strong P-gp/BCRP and CYP3A4 inhibitors, such as ketoconazole and ritonavir, can lead to a substantial increase in rivaroxaban exposure.

References

Touw DJ, Neef C, Thomson AH, Vinks AA, Cost-Effectiveness of Therapeutic Drug Monitoring Committee of The International Association For Therapeutic Drug Monitoring and Clinical Toxicology. Cost-effectiveness of therapeutic drug monitoring: A systematic review. Ther Drug Monit. 2005;27(1):10-7.

https://doi.org/10.1097/00007691-200502000-00004

Ghiculescu RA. Therapeutic drug monitoring: Which drugs, why, when, and how to do it. Austr Presc. 2008;31: 42‐44.

https://doi.org/10.18773/austprescr.2008.025

Gadepalli R. Therapeutic drug monitoring [Lecture notes on internet]. 2015. [access: 1 April 2024]. Available from: https://www. Slideshare.net/RamakanthGadepalli /therapeutic- drugmonitoring-52756284.

Kutt H, Winters W, Kokenge R, Mcdowell F. Diphenylhydantoin metabolism, blood levels and toxicity. Arch Neuro. 1964;11:642-8.

https://doi.org/10.1001/archneur.1964.00460240074010

Lund L. Anticonvulsant effect of diphenylhydantoin relative to plasma levels. A prospective three-year study in ambulant patients with generalized epileptic seizures. Arch Neurol. 1974;31(5):289-94.

https://doi.org/10.1001/archneur.1974.00490410037002

Zesh M. Anticoagulant drugs: Understanding their mechanism and clinical applications. Int Pediatr Research. 2023;6(3): 59-61.

https://doi.org/10.1358/dot.2023.59.1.3544242

Timothy E, Singh K, Moran A, Armbruster D, Kozuki N. Obstetric ultrasound use in low and middle income countries: a narrative review. Reprod Health. 2018;15:1-26.

https://doi.org/10.1186/s12978-018-0571-y

Melamed N, Baschat A, Yinon Y, Athanasiadis A, Mecacci F, Figueras F, et al. FIGO (International Federation of Gynecology and Obstetrics) initiative on fetal growth: Best practice advice for screening, diagnosis, and management of fetal growth restriction. Int J Gynaecol Obstet. 2021;152 Suppl 1(Suppl 1):3-57.

https://doi.org/10.1002/ijgo.13522

Lip GYH, Camm AJ, Hylek EM, Halperin JL, Weitz JI. Non-vitamin K antagonist oral anticoagulants: An appeal for consensus on terminology. Chest. 2014;145(5):1177-8.

https://doi.org/10.1378/chest.13-2951

Barnes GD, Ageno W, Ansell J, Kaatz S. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. Erratum in: J Thromb Haemost. 2015; 13(8):1539.

https://doi.org/10.1111/jth.13024

Samama MM. The mechanism of action of rivaroxaban--an oral, direct Factor Xa inhibitor--compared with other anticoagulants. Thromb Res. 2011;127(6):497-504.

https://doi.org/10.1016/j.thromres.2010.09.008

Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag. 2015;11:967-77.

https://doi.org/10.2147/TCRM.S84210

European Medicines Agency. Summary of product characteristics Xarelto. [accessed: 1 Mei 2024]. Available from: https://www.ema. europa.eu/en/documents/product- information/xareltoepar-product-information_en.pdf.

Titusville NJ, Jansenn. XARELTO® (rivaroxaban) safely and effectively. 2013. [access : 1 May 2024]. Available from:https://www.accessdata.fda.gov/drugsatfda_docs/ label/2011/202439s001lbl.pdf

Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-72.

https://doi.org/10.1161/CIRCULATIONAHA.113.004450

Turpie AG, Mason JA. Review of enoxaparin and its clinical applications in venous and arterial thromboembolism. Expert Opin Pharmacother. 2002;3(5):575-98. Erratum in: Expert Opin Pharmacother 2002;3(8):1233.

https://doi.org/10.1517/14656566.3.5.575

Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI. Antiplatelet drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e89S-e119S.

https://doi.org/10.1378/chest.11-2293

Gresham C, Levine M, Ruha AM. Case files of the medical toxicology fellowship at Banner Good Samaritan Medical Center in Phoenix, AZ: a non-warfarin anticoagulant overdose. J Med Toxicol. 2009;5:242-49.

https://doi.org/10.1007/BF03178275

Gerotziafas GT, Elalamy I, Depasse F, Perzborn E, Samama MM. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost. 2007;5(4):886-8.

https://doi.org/10.1111/j.1538-7836.2007.02429.x

Varin R, Mirshahi S, Mirshahi P, Chidiac J, Kierzek G, Marie J, et al. Effect of rivaroxaban, an oral direct factor Xa inhibitor, on whole blood clot permeation and thrombolysis: critical role of red blood cells. Blood. 2009;114.

https://doi.org/10.1182/blood.V114.22.1064.1064

Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412-21.

https://doi.org/10.1016/j.clpt.2005.06.011

Weitz JI, Jaffer IH, Fredenburgh JC. Recent advances in the treatment of venous thromboembolism in the era of the direct oral anticoagulants. F1000Res. 2017. 23;6:985.

https://doi.org/10.12688/f1000research.11174.1

Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939--an oral, direct factor Xa inhibitor after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12):873-80.

https://doi.org/10.1007/s00228-005-0043-5

Stampfuss J, Kubitza D, Becka M, Mueck W. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther. 2013;51(7):549-61.

https://doi.org/10.5414/CP201812

Weinz C, Buetehorn U, Daehler HP, Kohlsdorfer C, Pleiss U, Sandmann S, et al. Pharmacokinetics of BAY 59-7939--an oral, direct factor Xa inhibitor in rats and dogs. Xenobiotica. 2005;35(9):891-910.

https://doi.org/10.1080/00498250500250493

Bayer Pharma AG. Xarelto (rivaroxaban). Summary of Product Characteristics. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/000944/WC500057108.pdf

Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet. 2014;53(1):1-16.

https://doi.org/10.1007/s40262-013-0100-7

European Medicines Agency. CHMP assessment report for Xarelto. 2008. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_assessment_report/human/000944/WC5 00057122.pdf (Accessed 3 Mei 2024).

Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos. 2009; 37(5):1056-64.

https://doi.org/10.1124/dmd.108.025569

Kubitza D, Becka M, Roth A, Mueck W. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 2008; 24(10):2757-65.

https://doi.org/10.1185/03007990802361499

Sennesael AL, Larock AS, Douxfils J, Elens L, Stillemans G, Wiesen M, et al. Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study. Thromb J. 2018;12;16:28.

https://doi.org/10.1186/s12959-018-0183-3

Graff J, von Hentig N, Misselwitz F, Kubitza D, Becka M, Breddin HK, et al. Effects of the oral, direct factor xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol. 2007;47(11):1398-407.

https://doi.org/10.1177/0091270007302952

Kubitza D, Becka M, Roth A, Mueck W. The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct Factor Xa inhibitor. J Clin Pharmacol. 2013;53(3):249-55.

https://doi.org/10.1002/jcph.5

Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol. 2007;47(2):218-26.

https://doi.org/10.1177/0091270006296058

Jiang J, Hu Y, Zhang J, Yang J, Mueck W, Kubitza D, et al. Safety, pharmacokinetics and pharmacodynamics of single doses of rivaroxaban - an oral, direct factor Xa inhibitor-in elderly Chinese subjects. Thromb Haemost. 2010;103(1):234-41.

https://doi.org/10.1160/TH09-03-0196

Zhao X, Sun P, Zhou Y, Liu Y, Zhang H, Mueck W, et al. Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct factor Xa inhibitor rivaroxaban in healthy Chinese subjects. Br J Clin Pharmacol. 2009;68(1):77-88.

https://doi.org/10.1111/j.1365-2125.2009.03390.x

Fernandez S, Lenoir C, Samer CF, Rollason V. Drug-drug interactions leading to adverse drug reactions with rivaroxaban: A systematic review of the literature and analysis of vigi base. J Pers Med. 2021 30;11(4):250.

https://doi.org/10.3390/jpm11040250

Kubitza D, Becka M, Schwers S, Voith B. Investigation of pharmacodynamic and pharmacokinetic interactions between rivaroxaban and enoxaparin in healthy male subjects. Clin Pharmacol Drug Dev. 2013;2(3):270-7.

https://doi.org/10.1002/cpdd.26

Moore KT, Byra W, Vaidyanathan S, Natarajan J, Ariyawansa J, Salih H, et al. Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects. Br J Clin Pharmacol. 2015;79(6):907-17.

https://doi.org/10.1111/bcp.12559

Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban, an oral, direct factor Xa inhibitor, are not affected by aspirin. J Clin Pharmacol. 2006;46(9):981-90.

https://doi.org/10.1177/0091270006292127

Published
2025-01-07
Section
Articles