Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers.

Détails

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Etat: Public
Version: Final published version
ID Serval
serval:BIB_D520380EB7FC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers.
Périodique
Basic and Clinical Pharmacology and Toxicology
Auteur(s)
Ancrenaz V., Déglon J., Samer C., Staub C., Dayer P., Daali Y., Desmeules J.
ISSN
1742-7843 (Electronic)
ISSN-L
1742-7835
Statut éditorial
Publié
Date de publication
2013
Peer-reviewed
Oui
Volume
112
Numéro
2
Pages
132-137
Langue
anglais
Notes
Publication types: Controlled Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Résumé
The new anti-aggregating agent prasugrel is bioactivated by cytochromes P450 (CYP) 3A and 2B6. Ritonavir is a potent CYP3A inhibitor and was shown in vitro as a CYP2B6 inhibitor. The aim of this open-label cross-over study was to assess the effect of ritonavir on prasugrel active metabolite (prasugrel AM) pharmacokinetics in healthy volunteers. Ten healthy male volunteers received 10 mg prasugrel. After at least a week washout, they received 100 mg ritonavir, followed by 10 mg prasugrel 2 hr later. We used dried blood spot sampling method to monitor prasugrel AM pharmacokinetics (C(max) , t(1/2) , t(max) , AUC(0-6 hr) ) at 0, 0.25, 0.5, 1, 1.5, 2, 4 and 6 hr after prasugrel administration. A 'cocktail' approach was used to measure CYP2B6, 2C9, 2C19 and 3A activities. In the presence of ritonavir, prasugrel AM C(max) and AUC were decreased by 45% (mean ratio: 0.55, CI 90%: 0.40-0.7, p = 0.007) and 38% (mean ratio: 0.62, CI 90%: 0.54-0.7, p = 0.005), respectively, while t(1/2) and t(max) were not affected. Midazolam metabolic ratio (MR) dramatically decreased in presence of ritonavir (6.7 ± 2.6 versus 0.13 ± 0.07) reflecting an almost complete inhibition of CYP3A4, whereas omeprazole, flurbiprofen and bupropion MR were not affected. These data demonstrate that ritonavir is able to block prasugrel CYP3A4 bioactivation. This CYP-mediated drug-drug interaction might lead to a significant reduction of prasugrel efficacy in HIV-infected patients with acute coronary syndrome.
Mots-clé
Adult, Area Under Curve, Cross-Over Studies, Cytochrome P-450 CYP3A/metabolism, Cytochrome P-450 CYP3A Inhibitors, Drug Interactions, HIV Protease Inhibitors/pharmacokinetics, HIV Protease Inhibitors/pharmacology, Half-Life, Humans, Male, Midazolam/metabolism, Piperazines/pharmacokinetics, Prasugrel Hydrochloride, Ritonavir/pharmacology, Thiophenes/pharmacokinetics, Time Factors, Young Adult
Pubmed
Web of science
Open Access
Oui
Création de la notice
10/08/2016 11:22
Dernière modification de la notice
20/08/2019 16:54
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