(M1230-10-67) Rivaroxaban Pharmacokinetics after Single Oral Dose in Obese Subjects: An Open-Label Controlled Clinical Trial

Purpose: Anticoagulation therapy is the gold standard for the treatment and/or prevention of venous thromboembolism and atrial fibrillation. Direct oral anticoagulants (DOACs), including rivaroxaban, are increasingly preferred over conventional anticoagulants without the need for monitoring. DOACs dosing in obese subjects, however, remains a challenge due to the limited clinical data, and thus the evidence in this topic appears to be inconclusive. We aim to evaluate the pharmacokinetic profile of one of the DOACs, rivaroxaban, in obesity.

Methods: This is a controlled, open-label, parallel, single centre, single dose, fed-state clinical trial that compares rivaroxaban pharmacokinetic profile in healthy subjects who are obese vs. non-obese subjects. Healthy participants, aged 18-60 years old, were screened and divided into two groups depending on their body mass index, BMI (≥35 vs. 18.5-24.9 kg/m²). One film-coated tablet rivaroxaban 20 mg was administered orally to study participants. Blood samples were collected pre-dosing and at 1, 2, 4, 8, 12, 18, 36 and 48 hrs post dosing. Plasma was aliquoted from blood samples and kept in -80 °C until analysis. Rivaroxaban concentrations were measured in plasma samples using UPLC MS/MS. Pharmacokinetic profiles and parameters such as AUC_0®inf, AUC_0®t, C_max, T_max, V_d, Cl, and t_1/2 were determined using WinNonlin version 8.1.

Results: Thirty-six participants were recruited into the study, with 18 in each group. No significant difference in any of the pharmacokinetic parameters (Table 1) was detected including AUC_0®t (p=0.490), AUC_0®inf (p=0.678), C_max (p=0.059), T_max (p=0.515), V_d (p=0.473), Cl (p=0.614), and t_1/2 (p=0.310).

Conclusion: BMI/body weight did not have a significant impact on the pharmacokinetic primary parameters of rivaroxaban; and thus has minimal effect on rivaroxaban exposure. Therefore, fixed doses of rivaroxaban may be prescribed to patients without adjusting for body weight.

Acknowledgements:

Funding: This project is supported by Qatar University Student Grants [QUST-1-CPH-2023-843, QUST-2-CPH-2020-13] and QU Health Pump Priming Grant. We would like to thank our collaborators at The International Center for Bioavailability, Pharmaceutical, and Clinical Research in Cairo, Egypt, in which the study was conducted. Registration: The study is registered with The International Traditional Medicine Clinical Trial Registry [ISRCTN trial registration: ISRCTN12520248]. Ethics approvals: 1. Approved on Aug 17, 2022 by Qatar University IRB [P.O. Box 2713 Doha, Qatar; +974 (0)4403 5307; QU-IRB@qu.edu.qa], ref: QU-IRB 1741-E/22.; 2. Approved on Jul 25, 2022 by the Evaluation Unit of Bioavailability and Bioequivalence Studies for Human Pharmaceuticals [21 Abdel Aziz Al Saud St., Manial Al-Rawda, Cairo, Egypt; +202 (0) 25354100 ext: 1806; info@edaegypt.gov.eg].; 3. Approved on Jun 29, 2022 by the International Centre for Bioavailability, Pharmaceutical and Clinical Research IRB [North Industrial Zone, El Obour City, Cairo, Egypt; +20 (0)2 44891734; ahmed. ismail@hu.edu.eg], ref: FORM04/SOP: QA-0321.

Table 1. Summary of the pharmacokinetic parameters achieved after rivaroxaban 20 mg oral administration in non-obese and obese subjects.
Footnote: *Independent sample t-test. AUC0inf: area under concentration-time curve from time zero to infinity; AUC0last: area under concentration-time curve from time zero to the last measurable concentration; Cmax: maximum plasma concentration; Tmax: time at the maximum plasma concentration; Vd: volume of distribution; t1/2: half-life; MRT: mean residence time.