THE EFFECT OF OBESITY ON RIVAROXABAN PHARMACOKINETICS AND PHARMACODYNAMICS

Abstract

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a prevalent condition that is associated with high rates of morbidity and mortality worldwide. Similarly, atrial fibrillation (AF) is one of the most common sustained heart arrhythmias, with an increased prevalence over the last two decades. Anticoagulation therapy is the cornerstone in the treatment and prevention of VTE, and the prevention of stroke in patients with non-valvular AF. Direct oral anticoagulants (DOACs) - including rivaroxaban - are a novel class of anticoagulants which have overcome the limitations of the traditional anticoagulants (warfarin and heparins) and have demonstrated superior safety and efficacy in general population. Rivaroxaban is a selective and direct inhibitor of factor Xa in the coagulation process. Despite the fact that obesity is a risk factor for VTE onset and recurrence and that a large proportion of obese patients who have VTE or AF need to use DOACs for anticoagulation, there is a conflicting evidence in terms of rivaroxaban pharmacokinetics (PK) and dosing in the obese population. We have conducted a three-phase research project to investigate the effect of obesity on the PK and the pharmacodynamics (PD) of rivaroxaban. Phase One was a systematic review that aimed to compile the available evidence regarding rivaroxaban PK in obese vs. non-obese populations, and it revealed that obesity has a variable impact on rivaroxaban PK parameters. Phase Two was a pharmacoepidemiologic retrospective cohort study that investigated prescribing trends and clinical outcomes based on BMI categorization in patients who received rivaroxaban. The findings revealed that rivaroxaban prescribing trend had increased significantly from 2015 to 2020. Furthermore, morbidly obese patients receiving rivaroxaban therapy were at a significantly higher risk of all-cause mortality compared with lower BMI categories. Finally, Phase Three was a prospective, parallel-group, single-dose, fed-state controlled clinical PK and PD study that included healthy male subjects who were assigned in one of two groups: obese subjects with BMI ≥35 kg/m2 and normal-weight control subjects with BMI of 18.5 to <25 kg/m2. After administration of a single oral dose of rivaroxaban 20 mg, nine blood samples and multiple urine samples were collected over 48 hr, and the samples were analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometer to obtain rivaroxaban concentrations. The findings revealed that the pharmacokinetic parameters, including, maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under the plasma concentration vs. time curve from zero to 48 hr (AUC0-48) and from zero to infinity (AUC0-inf), elimination rate constant (ke), half-life (t1/2), mean residence time (MRT), apparent volume of distribution (Vd/F), apparent clearance (Cl/F), and fraction of dose recovered unchanged in urine over the urine collection period (fe), as well as the pharmacodynamic parameters (prothrombin time [PT], international normalized ratio [INR], and activated partial thromboplastin clotting time [aPTT]) were mostly similar in obese compared to non-obese subjects. Overall, the results suggest that the standard dosing regimen of rivaroxaban may be applied uniformly across both obese and non-obese subjects, eliminating the need for rivaroxaban dose adjustments based on body weight. The findings of the last phase can be complemented by robust PK studies in diseased populations and using multiple doses of rivaroxaban.