Clopidogrel increased dasabuvir AUC 4.7-fold compared with placebo (P=8·10^-7), and ritonavir decreased clopidogrel active metabolite AUC by 51% (P=0.0001).
RCT (n=12)
Crossover
Does the coadministration of clopidogrel and ritonavir alter the pharmacokinetics of dasabuvir and the antiplatelet efficacy of clopidogrel in healthy subjects?
Coadministration of clopidogrel and ritonavir leads to clinically significant drug-drug interactions, markedly increasing dasabuvir concentrations and reducing clopidogrel's antiplatelet efficacy.
Effect estimate: 4.7-fold increase
p-value: p=8·10^-7
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‐∞ of dasabuvir 4.7‐fold; range 2.0–10.1‐fold ( P = 8·10 −7 ), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC 0‐∞ 3.9‐fold; range 2.1–7.9‐fold ( P = 2·10 −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.
Itkonen et al. (Thu,) conducted a rct in Healthy subjects (n=12). Clopidogrel and ritonavir vs. Placebo was evaluated on Dasabuvir AUC 0-∞ (4.7-fold increase, p=8·10^-7). Clopidogrel increased dasabuvir AUC 4.7-fold compared with placebo (P=8·10^-7), and ritonavir decreased clopidogrel active metabolite AUC by 51% (P=0.0001).