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Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel
Tekijät: Itkonen MK, Tornio A, Lapatto-Reiniluoto O, Neuvonen M, Neuvonen PJ, Niemi M, Backman JT
Kustantaja: WILEY
Julkaisuvuosi: 2019
Journal: Clinical Pharmacology and Therapeutics
Tietokannassa oleva lehden nimi: CLINICAL PHARMACOLOGY & THERAPEUTICS
Lehden akronyymi: CLIN PHARMACOL THER
Vuosikerta: 105
Numero: 1
Aloitussivu: 219
Lopetussivu: 228
Sivujen määrä: 10
ISSN: 0009-9236
DOI: https://doi.org/10.1002/cpt.1099
Tiivistelmä
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.
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.
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