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

Show full item record



Permalink

http://hdl.handle.net/10138/296443

Citation

Itkonen , M K , Tornio , A , Lapatto-Reiniluoto , O , Neuvonen , M , Neuvonen , P J , Niemi , M & Backman , J T 2019 , ' Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel ' , Clinical Pharmacology and Therapeutics , vol. 105 , no. 1 , pp. 219-228 . https://doi.org/10.1002/cpt.1099

Title: Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel
Author: Itkonen, Matti K.; Tornio, Aleksi; Lapatto-Reiniluoto, Outi; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T.
Contributor organization: HUSLAB
Department of Clinical Pharmacology
University of Helsinki
Clinicum
Medicum
Janne Backman / Principal Investigator
Date: 2019-01
Language: eng
Number of pages: 10
Belongs to series: Clinical Pharmacology and Therapeutics
ISSN: 0009-9236
DOI: https://doi.org/10.1002/cpt.1099
URI: http://hdl.handle.net/10138/296443
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.
Subject: DRUG-DRUG INTERACTION
ACTING ANTIVIRAL REGIMEN
PLASMA-CONCENTRATIONS
MARKEDLY INCREASES
CYTOCHROME-P450 3A
PLUS DASABUVIR
PHARMACOKINETICS
OMBITASVIR
PARITAPREVIR/RITONAVIR
PHARMACODYNAMICS
317 Pharmacy
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: publishedVersion


Files in this item

Total number of downloads: Loading...

Files Size Format View
Itkonen_et_al_2 ... rmacology_Therapeutics.pdf 1019.Kb PDF View/Open

This item appears in the following Collection(s)

Show full item record