Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Clin Pharmacol Ther. 2019 Jan;105(1):219-228. doi: 10.1002/cpt.1099. Epub 2018 Aug 9.
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 of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8·10 ), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC 3.9-fold; range 2.1-7.9-fold (P = 2·10 ), compared with ritonavir alone. Ritonavir decreased the AUC 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.
达沙布韦主要通过细胞色素 P450（CYP）2C8 代谢，主要与利托那韦联合使用。利托那韦和氯吡格雷分别是 CYP3A4 和 CYP2C8 的抑制剂。在 12 名健康受试者的一项随机交叉研究中，我们研究了临床剂量的利托那韦（5 天）、氯吡格雷（3 天）及其联合用药对达沙布韦药代动力学的影响，以及利托那韦对氯吡格雷的影响。与安慰剂相比，氯吡格雷而非利托那韦使达沙布韦的几何均数 AUC 增加了 4.7 倍；范围 2.0-10.1 倍（P = 8·10）。氯吡格雷和利托那韦联合用药使达沙布韦 AUC 增加了 3.9 倍；范围 2.1-7.9 倍（P = 2·10），与单独使用利托那韦相比。利托那韦使氯吡格雷活性代谢物的 AUC 降低了 51%（P = 0.0001），且平均血小板抑制率从无利托那韦时的 51%降至有利托那韦时的 31%（P = 0.0007）。总之，氯吡格雷显著升高了达沙布韦的浓度，而接受利托那韦治疗的患者可能存在氯吡格雷反应减弱的风险。
