Pharmacokinetics/Pharmacodynamics, Safety, and Tolerability of Rivaroxaban with Cobicistat or Darunavir/Cobicistat in Healthy Participants

Background: Direct oral anticoagulants such as rivaroxaban are a feasible and convenient option for anticoagulation in people living with HIV. Here, we assess the effect of cobicistat or darunavir/cobicistat on the pharmacokinetics (PK), pharmacodynamics (PD), and safety of rivaroxaban. Methods: This open-label, fixed sequence, intrasubject drug-drug interaction PK study enrolled healthy participants who received oral study drugs sequentially as follows: rivaroxaban 10 mg once on day 1, cobicistat 150 mg once-daily on days 2 to 7, rivaroxaban 10 mg once on day 7, darunavir/cobicistat 800/150 mg once-daily on days 8 to 13 followed by rivaroxaban 10 mg once on day 13. Serial PK and PD plasma samples were obtained on days 1, 7, and 13 over 24 hours. Safety was assessed throughout the study. Results: Twelve participants enrolled and completed three phases of the study. Rivaroxaban geometric mean ratios (GMR, rivaroxaban + cobicistat versus rivaroxaban alone) and 90% confidence interval (CI) for C max and AUC 0-∞ were 1.50 (1.10-1.90) and 2.14 (1.70-2.58), respectively. Rivaroxaban GMR (rivaroxaban + darunavir/cobicistat versus rivaroxaban alone) and 90% CI for C max and AUC 0-∞ were 1.53 (1.13-1.94) and 2.12 (1.68-2.56), respectively. Rivaroxaban concentrations were positively correlated with PD markers in a linear fashion and returned to near-baseline 24 hours post-dose. All adverse events were mild to moderate in severity and resolved by the end of the study. Conclusion: Coadministration of cobicistat and cobicistat-boosted darunavir with rivaroxaban resulted in a clinically significant increase in rivaroxaban drug exposure. Further study can inform safety and efficacy of rivaroxaban dose reduction.