Lopinavir / ritonavir

Dabigatran

Clinically significant interaction is unlikely.

No pharmaceutical opinion available for this interaction.

Mechanism

Lopinavir / ritonavir can inhibit the intestinal P-gp and increase the plasma concentration of Dabigatran.

Lopinavir / ritonavir

Pharmacodynamic effects

Recommendations

Alternative solution(s)

Dabigatran

Pharmacodynamic effects

Probably without any clinical consequence.

Recommendations

No a priori dosage adjustment is recommended.

See comments.

Alternative solution(s)

Prefer warfarin or low molecular weight heparin (LMWH).

Monitor

Adverse effects of dabigatran: Bleeding (suspect bleeding if there is a drop in hemoglobin and/or hematocrit or hypotension), anemia, hematoma, hematuria, epistaxis, gastrointestinal disorders (abdominal pain, diarrhea, dyspepsia and nausea), gastrointestinal and urinary hemorrhage.

Tests

Pharmacokinetic parameters

Comment

Some studies have shown a significant increase in dabigatran bioavailability when administered with P-gp inhibitors. While others showed no interaction.

Ref #3341 : Contrary to expectations, in a study with 16 healthy subjects, no significant changes in dabigatran exposure were observed with simultaneous ritonavir administration, possibly due to mixed induction and inhibition of P-gp by ritonavir. Researchers conclude that dabigatran could likely be co-administred with ritonavir.

Ref # 3133: In addition, a sub-analysis of the Re-Ly study (18,113 patients with atrial fibrillation receiving dabigatran 150 or 110 mg BID) mentions that P-gp inhibitors modestly increase dabigatran plasma concentration and that the risk of major bleeding and stroke was not different between patients on warfarin and dabigatran patients with concomitant use of P-gp inhibitors.

Ref #3158 : Case report showed no interaction when dabigatran administered to a patient on lopinavir/ritonavir. In this case report the patient had initially received 75 mg BID with low Cmin measured. With 110 mg BID dose, measured concentration was comparable to the concentrations obtained in the Re-Ly study.

Ref #3398 : Case report of a 60-year old HIV+ man taking combined antiretroviral therapy (containing atazanavir/ritonavir) with concomitant use of dabigatran. Combination was tolerated, dabigatran blood levels within the expected range and there was no evidence of bleeding or other adverse effects. This case suggests that dabigatran may be a viable option.

Ref #3399 : Another case report showed no interaction when using dabigatran with darunavir/ritonavir.

The product monograph recommended dose adjustments when used for prevention of venous thrombophlebitis after surgery:
A. With potent P-gp inhibitors (as ketoconazole): Avoid administration.
B. With P-gp inhibitors (amiodarone, quinidine, verapamil°): Consider dose reduction. See product monograph for indications.
C. With P-gp inhibitors (amiodarone, quinidine, vérapamil°) and moderate renal impairment (ClCre 30-50 ml/min) : Consider a greater dose reduction. See product monograph for indications.
D. With other P-gp inhibitors (cyclosporine, itraconazole, posaconazole, nelfinavir, ritonavir, saquinavir) : Exercer un suivi plus étroit.
° For verapamil, it is also recommended to avoid concurrent administration. Give dabigatran 2 hours before verapamil.

Reference
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    Egan G, Hughes CA, Ackman ML. Drug interactions between antiplatelet or novel anticoagulant medications and antiretroviral medications. Ann Pharmacother. 2014 Jun; 48 (6): 734-40.
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    INESSS : Anticoagulothérapie par le dabigatran. Décembre 2011. http://www.inesss.qc.ca/fileadmin/doc/INESSS/Outils/Pradax/Pradaxa_FINAL_201205_FR.pdf
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  • 3133
    Reilly PA, Connolly SJ, Ezekowitz MD, Haertter S, Noack H, Wallentin L, Yusuf S Concomitant use of Pglycoprotein inhibitors with dabigatran or warfarin in the RE-LY trial. ESC 2011, 33rd Cong of the European Society of Cardiology (ESC), Paris, 27-31 Aug 2011. Eur Heart J 32 (Suppl 1), 6 (2011).
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    Kumar P, Gordon LA, Brooks KM, George JM, Kellogg A et al. Differential influence of the antiretroviral pharmacokinetic enhancers ritonavir and cobicistat on intestinal P-glycoprotein transport and the pharmacokinetic/pharmacodynamic disposition of dabigatran. Antimicrob Agents Chemother. 2017 Oct 24; 61(11).
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    Kakadiva PP, Higginson RT and Fulco PP. Ritonavir-Boosted Protease Inhibitors but Not Cobicistat Appear Safe in HIV-Positive Patients Ingesting Dabigatran. Antimicrob agents Chemother 2018 Jan 25; 62(2).