Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel

Abstract

Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC(0-infinity) of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8 center dot 10(-7)), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC(0-infinity) 3.9-fold; range 2.1-7.9-fold (P = 2 center dot 10(-6)), compared with ritonavir alone. Ritonavir decreased the AUC(0-4h) of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.