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

• Published in: Clinical pharmacology and therapeutics Vol. 105; no. 1; pp. 219 - 228
• Main Authors: Itkonen, Matti K., Tornio, Aleksi, Lapatto‐Reiniluoto, Outi, Neuvonen, Mikko, Neuvonen, Pertti J., Niemi, Mikko, Backman, Janne T.
• Format: Journal Article
• Language: English
• Published: United States 01.01.2019
• Subjects: Adult; Clopidogrel - administration & dosage; Clopidogrel - blood; Cross-Over Studies; Cytochrome P-450 CYP3A Inhibitors - administration & dosage; Cytochrome P-450 CYP3A Inhibitors - blood; Drug Synergism; Drug Therapy, Combination; Female; Humans; Male; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - blood; Ritonavir - administration & dosage; Ritonavir - blood; Sulfonamides - administration & dosage; Sulfonamides - blood; Uracil - administration & dosage; Uracil - analogs & derivatives; Uracil - blood; Young Adult
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1002/cpt.1099

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 AUC0‐∞ of dasabuvir 4.7‐fold; range 2.0–10.1‐fold (P = 8·10−7), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC0‐∞ 3.9‐fold; range 2.1–7.9‐fold (P = 2·10−6), compared with ritonavir alone. Ritonavir decreased the AUC0‐4h 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.