Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran

Abstract

Dabigatran etexilate (DE) is a P-glycoprotein (P-gp) probe substrate, and its active anticoagulant moiety, dabigatran, is a substrate of the multidrug and toxin extrusion protein-1 (MATE-1) transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE at 150 mg alone, followed by ritonavir at 100 mg or cobicistat at 150 mg daily for 2 weeks. DE was then given 2 h before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran pharmacokinetic (PK) exposure or thrombin time (TT) measures were observed with the simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean decrease in dabigatran PK exposure of 29% (90% confidence interval [CI], 18 to 40%) but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (area under the concentration-versus-time curve from time zero to infinity and maximum plasma concentration) by 127% each (90% CI, 81 to 173% and 59 to 196%, respectively) and increased TT measures (33% for the area-under-the-effect curve from time zero to 24 h [90% CI, 22 to 44%] and 51% for TT at 24 h [90% CI, 22 to 78%]) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by 2 h from the administration of dabigatran. In all comparisons, no significant increase in the dabigatran elimination half-life was observed. Therefore, it is likely safe to coadminister ritonavir with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with the coadministration of cobicistat due to the greater net inhibition of intestinal P-gp transport and increased bioavailability. (This study has been registered at ClinicalTrials.gov under identifier NCT01896622.).

Keywords: ABC transporters; DOACs; MATE-1; P-gp; anticoagulants; antiretroviral; antiretroviral agents; boosting agents; cobicistat; dabigatran; drug transport; drug-drug interaction; pharmacodynamics; pharmacokinetic enhancers; pharmacokinetics; ritonavir; thrombin time; transporters.

This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

Figures

FIG 1

Mean ± SEM dabigatran concentration-versus-time curves after administration of dabigatran alone, administration of dabigatran separated by 2 h from administration of ritonavir (RTV) (A) or cobicistat (COBI) (B), and simultaneous administration of dabigatran with ritonavir (A) and cobicistat (B). DE, dabigatran etexilate.

FIG 2

Median ± 90% confidence interval thrombin time-versus-time curves after administration of dabigatran alone, administration of dabigatran separated by 2 h from administration of ritonavir (RTV) (A) or cobicistat (COBI) (B), and simultaneous administration of ritonavir (A) and cobicistat (B). DE, dabigatran etexilate.

FIG 3

Study design. Abbreviations: COBI, cobicistat; DE, dabigatran etexilate; PD, pharmacodynamics; PK, pharmacokinetics; RTV, ritonavir.