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Lopinavir / ritonavir can inhibit the intestinal P-gp and increase the plasma concentration of Dabigatran.
3A4 (major), 13 identified metabolites, 5 of these metabolites are linked to the metabolism of ritonavir, transporters: MRP1, MRP2, OATP1A2, OATP1B1, P-gp
2C19 (strong), 1A2, 2C9 (moderate) UGT (moderate)
3A4 and 2D6 (strong), transporters: BCRP, MRP2, OATP1A2, OATP1B1, OATP1B3, OATP2B1, P-gp
P-gp and MATE-1, mainly eliminated in the urine (85%).
Possible increase of adverse effects.
No a priori dosage adjustment is recommended.
Use with caution when co-administered with a P-gp inhibitor especially in patients with mild or moderate renal impairment.
Monitor for adverse effects.
A decrease in dosage may be necessary.
Prefer warfarin or low molecular weight heparin (LMWH).
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.
Ref #2368 : Some studies have shown a significant increase in dabigatran bioavailability when administered with P-gp inhibitors (ketoconazole and glecaprévir/pibrentasvir). The product monograph recommends caution when co-administering certain P-gp inhibitors, including but not limited to cyclosporine, itraconazole, nelfinavir, posaconazole, ritonavir, saquinavir, tacrolimus and tipranavir as they may increase systemic exposure to dabigatran.
Ref #3341 : Contrary to expectations, in this 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 ritonavir100 mg QD in patients with no renal impairment.
Note: Co-administration of dabigatran with higher daily doses of ritonavir has not been studied.
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.