Differential Influence of Antiretroviral PK Enhancers, Ritonavir and Cobicistat, on Intestinal P-Glycoprotein Transport and the PK/PD Disposition of Dabigatran [PublishAheadOfPrint]

Dabigatran etexilate (DE) is a P-gp probe substrate and its active anticoagulant moiety, dabigatran, is a substrate of the MATE-1 transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE 150mg alone, followed by ritonavir 100mg or cobicistat 150mg daily for two weeks. DE was then given two hours before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran PK exposure or thrombin time (TT) measures were observed with simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean (90% Confidence Interval [CI]) 29% [18-40%] decrease in dabigatran PK exposure, but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (AUC_0- and C_max by 127% each [90% CI: 81-173% and 59-196%, respectively]) and increased TT measures (AUEC_0-24 and TT₂₄ by 33% [22-44%] and 51% [22-78%], respectively) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by two hours from dabigatran. In all comparisons, there was no significant change observed in dabigatran elimination half-life. Therefore, ritonavir is likely safe to coadminister with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with co-administration of cobicistat due to greater net inhibition of intestinal P-gp transport and increased bioavailability.

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