Rivaroxaban Pharmacokinetics in Obese Subjects: A Systematic Review

Abstract

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality globally. The direct oral anticoagulants, including rivaroxaban, are relatively novel therapeutic options in the treatment and prevention of VTE. There is a conflicting and inconclusive evidence surrounding the pharmacokinetics (PK) of rivaroxaban in patients with VTE who are obese. We conducted a systematic review to provide an overview, and to synthesize the available evidence in the current literature pertaining to rivaroxaban PK in obese subjects who are healthy or diseased. The PubMed, Embase, ScienceDirect, Rayyan, and Cochrane Library databases were systematically searched from 1 May 2021 through 28 February 2022. Studies investigating rivaroxaban PK in adult obese subjects were included in the review. Pertinent data, including anthropometric parameters, rivaroxaban dosage regimen, PK parameters, PK model, and outcome measures were extracted. Reference values of rivaroxaban PK parameters in the general population were used for comparison purposes. The review protocol was registered in the PROSPERO database (CRD42020177770). In the 11 studies included in this systematic review, over 7140 healthy or diseased subjects received rivaroxaban therapy, with varying clinical indications in the diseased population. The reported PK parameters of rivaroxaban in obese subjects compared with reference values in the general population were variable. The reported values of the volume of distribution (V) among obese subjects (73.4-82.8 L) fell within the range of values reported/calculated for the general population (59.4-104 L), assuming complete bioavailability. However, some of the reported values of clearance (CL) in obese subjects (7.86-16.8 L.h) do not fall within the range of values reported/calculated for the general population (5.57-11.3 L.h). The reported maximum plasma concentrations in obese subjects versus the general population following a 10 mg dose were 149 vs. 143-180 µg.L, and following a 20 mg dose were 214-305 vs. 299-360 µg.L, respectively. The area under the plasma concentration versus time curves (AUC) over different intervals in obese subjects versus the general population following a 10 mg dose were 1155 (AUC from time zero to infinity [AUC]) vs. 1029 (AUC) µg.h.L; and 1204-2800 (AUC from time zero to 24 h [AUC]) vs. 3200 (AUC) µg.h.L, respectively, following a 20 mg dose. The reported values of half-life and time to reach the maximum plasma concentration in obese subjects versus the general population were not consistent across studies. Variable changes and inconsistencies in different rivaroxaban PK parameters were reported in obese subjects. Further well-designed studies are warranted to better characterize the PK and clinical outcomes of rivaroxaban in subjects with obesity.