Antiretroviral Boosting Agent Cobicistat Increases the Pharmacokinetic Exposure and Anticoagulant Effect of Dabigatran in HIV-Negative Healthy Volunteers
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- drug-drug interaction
- thrombin time
Drug 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 antiretroviral-boosting 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 alterations in drug elimination occurred, significant increases were observed in oral bioavailability (data not shown). Additionally, the anticoagulant effect correspondingly increased, with 33% and 51% increases in the geometric mean area-under-the-TT-effect-versus-time curve and TT at 24 hours after dose, respectively (P<0.001). Separation of administration by 2 hours (Phase 2) minimally mitigated this interaction, with increases in the geometric mean area-under-the-concentration-versus-time curve from zero to infinity, maximal concentration, area-under-the-TT-effect-versus-time curve, and TT at 24 hours after dose of 110%, 99%, 30%, and 46% (P<0.001 for all comparisons), respectively (Figure 1A and 1B). In fact, no significant difference in pharmacokinetic or TT parameters was noted between simultaneous (Phase 3) and separated (Phase 2) administration of cobicistat and dabigatran.
Previous investigations with intestinal P-gp transporter inhibitors have resulted in increased dabigatran drug exposure and corresponding anticoagulation activity. Härtter et al3 illustrated that this interaction could potentially be obviated by separating administration by 2 hours. In our study, simultaneous cobicistat and dabigatran administration resulted in significant increases in dabigatran exposure and TT measures. However, separated administration by 2 hours was inadequate for circumventing this interaction. Because participants typically experienced maximal dabigatran concentrations 3 to 4 hours after dosing, it is possible that separated administration by ≥4 hours may have circumvented the interaction. However, this strategy may present a considerable challenge for adherence with standard twice-daily dabigatran administration.
The true clinical impact on dabigatran’s anticoagulant effects may be larger than we measured with the TT assay, STA-Thrombin, which reports a maximum TT value of 120 seconds. Furthermore, this study was conducted in healthy volunteers, as is standard in most drug interaction studies; it is plausible that patients infected with HIV may have altered susceptibility to this interaction. Kis et al4 showed that treatment-experienced patients with HIV have increased P-gp gene expression (3.2-fold) compared with treatment-naïve patients with HIV. Initiation with 110 mg daily and subsequent titration of dose based on dabigatran concentrations was successfully used in a patient infected with HIV; however, this patient was receiving a different antiretroviral boosting agent, ritonavir, which is known to demonstrate mixed P-gp inhibition and induction.2,5
Nonetheless, these findings support the need for future investigations conducted in patients receiving concomitant dabigatran and cobicistat to determine whether dose adjustment is clinically indicated and/or effective. It is important to note that all currently available alternative direct oral anticoagulants (rivaroxaban, apixaban, and edoxaban) are expected to interact with cobicistat because of cytochrome P450 3A4 inhibition, leaving subcutaneous enoxaparin or INR-monitored warfarin as the remaining chronic anticoagulant options. Fortunately, the availability of idarucizumab for rapid reversal of anticoagulation may be considered a layer of safety in patients receiving cobicistat-boosted antiretrovirals and dabigatran.
Lori A. Gordon, PharmD
Parag Kumar, PharmD
Kristina M. Brooks, PharmD
Anela Kellogg, MSN
Maryellen McManus, MPH
Raul M. Alfaro, MS
Khanh Nghiem, MS
Jomy M. George, PharmD
Jay Lozier, MD, PhD
Scott R. Penzak, PharmD
Colleen Hadigan, MD, MPH
Sources of Funding
Funding for this study was provided by the National Institutes of Health Clinical Center Pharmacy Department and the National Institute of Allergy and Infectious Diseases intramural research program.
*Drs Gordon and Kumar contributed equally.
Some of the data contained in this manuscript were previously presented in abstract form at the annual Conference on Retroviruses and Opportunistic Infections in February 2016 in Boston, MA.
Circulation is available at http://circ.ahajournals.org.
- © 2016 American Heart Association, Inc.
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