Liverpool HIV Interactions

Potential Interaction

Darunavir/cobicistat (DRV/c)

Dabigatran

Quality of Evidence: Low

Summary:

Coadministration of dabigatran (150 mg) and darunavir/cobicistat (800/150 mg single dose and multiple doses once daily) was studied in 14 subjects. Single dose administration increased dabigatran AUC and Cmax by 164% and 164%, whereas dabigatran AUC and Cmax increased by 88% and 99% with darunavir/cobicistat once daily. The effect of separating dosing was studied using cobicistat alone. Coadministration of dabigatran (150 mg single dose) simultaneously with or 2 h before cobicistat alone (150 mg once daily) was studied in HIV negative subjects. Simultaneous administration increased dabigatran AUC by 127% (n=16). Separating the dosing by 2 h did not overcome the interaction (dabigatran AUC increased by 110%, n=18). This pharmacokinetic interaction (due to inhibition of intestinal P-gp by cobicistat) resulted in a more pronounced anticoagulant response as indicated by measurements of the thrombin times. A population/PBPK/PD analysis indicates that in presence of cobicistat, the dabigatran dose should be reduced to 110 mg twice daily in individuals with normal renal function and to 75 mg twice daily in individuals with moderate renal impairment, and that coadministration should be avoided in case of severe renal impairment.

Description:

Clinical monitoring and dose reduction is required when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate, is co administered with darunavir/cobicistat. Co-administration of dabigatran etexilate (150 mg) and darunavir/cobicistat (800/150 mg single dose) increased dabigatran AUC and Cmax by 164% and 164%. Co-administration of dabigatran etexilate (150 mg) and darunavir/cobicistat (800/150 mg once daily) increased dabigatran AUC and Cmax by 88% and 99%.

Rezolsta Summary of Product Characteristics, Janssen-Cilag Ltd, July 2023.

A drug-drug interaction study between darunavir/cobicistat and dabigatran etexilate (150 mg) was conducted in 14 healthy participants. Co-administration of darunavir/cobicistat (800/150 mg single dose) increased dabigatran Cmax and AUC by 164% and 164%. Co-administration of darunavir/cobicistat (800/150 mg once daily) increased dabigatran Cmax and AUC by 99% and 88%. Refer to the dabigatran etexilate prescribing information for recommendations regarding co-administration. The specific recommendations are based on indication, renal function, and effect of the coadministered P-gp inhibitors on the concentration of dabigatran. Clinical monitoring is recommended when a DOAC not affected by CYP3A4 but transported by P-gp, including dabigatran etexilate, is co-administered with darunavir/cobicistat.

Prezcobix US Prescribing Information, Janssen Pharmaceuticals Inc, March 2023.

Coadministration of dabigatran (150 mg single dose) simultaneously with, or 2 h before cobicistat (150 mg once daily) was studied in HIV negative subjects. Simultaneous administration increased both dabigatran AUC and Cmax by 127% (n=16). Separating the dosing by 2 h did not overcome the interaction (dabigatran AUC and Cmax increased by 110% and 99%, n=18). This pharmacokinetic interaction (due to inhibition of intestinal P-glycoprotein by cobicistat) resulted in a more pronounced anticoagulant response as indicated by measurements of the thrombin times. Further studies are required to determine if staggering administration by 4 h or more may overcome the interaction since maximal dabigatran concentrations occur 3-4 h post dose.

Antiretroviral boosting agent cobicistat increases the pharmacokinetic exposure and anticoagulant effect of dabigatran in HIV-negative healthy volunteers. Gordon LA, Kumar P, Brooks KM, et al. Circulation, 2016, 134(23): 1909-1911.

A population/physiologically based pharmacokinetic/pharmacodynamics analysis evaluated changes in dabigatran exposure in presence of cobicistat and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within one year. The model indicated that coadministration of dabigatran and cobicistat should be avoided in subjects with severe renal impairment. The dabigatran dose should be reduced to 75 mg twice daily when coadministered with cobicistat in subjects with moderate renal impairment and should be reduced to 110 mg twice daily when coadministered with cobicistat in individuals with normal renal function.

Quantitative benefit-risk assessment of P-gp mediated drug-drug interactions (DDIs) of dabigatran co-administered with pharmacokinetic enhancers in patients with renal impairment. Lingineni K, Farhan N, Kim S, et al. Clin Pharmacol Ther, 2021; 109(1):193-200.

View all available interactions with Darunavir/cobicistat (DRV/c) by clicking here.