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Antiretroviral Boosting Agent Cobicistat Increases the Pharmacokinetic Exposure and Anticoagulant Effect of Dabigatran in HIV-Negative Healthy Volunteers

Year: 2016

Type: article

Abstract: rug interactions between antiretroviral therapy and anticoagulant medications are of particular concern given that ≈50% of the current HIV population is >50 years of age.Moreover, HIV infection is characterized by a hypercoaguable state and premature immunologic aging, in which thromboembolic events may be as much as 10 times more prevalent than in the general population across all age spectra. 1 Dabigatran was the first direct oral anticoagulant approved by the US Food & Drug Administration and is the only direct oral anticoagulant with a US Food & Drug Administration -approved specific reversal agent, idarucizumab.Unlike warfarin and many other direct oral anticoagulants, dabigatran is not a substrate, inhibitor, or inducer of cytochrome P450 metabolic enzymes.However, dabigatran is a substrate of Permeability-glycoprotein (P-gp) and renal multidrug and toxin extrusion-1 transporters.Cobicistat is a US Food & Drug Administration -approved antiretroviralboosting agent that is coformulated with numerous fixed-dose combination antiretroviral products because of its inhibitory effects on cytochrome P450 3A4.Currently, ≈40% of all treatment-naïve patients with HIV in the United States are initiated on a cobicistat-boosted antiretroviral regimen.In addition to cytochrome P450 3A4, cobicistat is also an inhibitor of both P-gp and multidrug and toxin extrusion-1 transporters.2 Thus, this study aimed to determine whether the coadministration of cobicistat increases the systemic exposure and anticoagulant effects of dabigatran and, if so, whether separating administration would circumvent this interaction.This open-label, single-sequence drug interaction study was conducted in healthy HIV-negative volunteers (Clinical Trial Registration: URL: https://www.clinicaltrials.gov, Unique identifier: NCT01896622).All participants gave written informed consent, and the study was approved by the National Institute of Allergy and Infectious Diseases Institutional Review Board.Participants first received a single dose of dabigatran 150 mg alone (Phase 1).After a 5-day washout period, participants then began cobicistat 150 mg daily.After 2 weeks, a second single dose of dabigatran was given 2 hours before cobicistat (Phase 2), and then 1 week later, a third single dose of dabigatran was given simultaneously with cobicistat (Phase 3).After each dabigatran dose, blood was collected serially over 24 hours for pharmacokinetic and thrombin time (TT) analysis (STA-Thrombin assay, Diagnostica Stago, Inc.), including area-under-the-concentration-versus-time curve from time zero to infinity, maximal concentration, area-under-the-TT-effect-versus-time curve, and TT at 24 hours after the dose with Phoenix WinNonlin software (v6.4).P values were calculated by paired Student t tests (Microsoft Excel).Sixteen participants completed all phases of the study, and an additional 2 completed Phases 1 and 2 only.Simultaneous administration of cobicistat (Phase 3) resulted in significant increases in dabigatran pharmacokinetic exposure, with a 127% increase in both the geometric mean area-under-the-concentration-versus-time curve from time zero to infinity and maximal concentration (P<0.001).Although no altera-

Source: Circulation

DOI: 10.1161/circulationaha.116.025257