Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers

Article Article scientifique Article Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers eng 2013 author Ancrenaz Virginie 706427 author Deglon Julien 623118 author Samer Caroline Flora 0000-0001-8178-0616 105661 author Staub Christian Olivier 82799 author Dayer Pierre 25460 author Daali Youssef 46042 author Desmeules Jules Alexandre 73542 132-137 10.1111/j.1742-7843.2012.00932.x 22900583 1742-7835 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. Dewey 615 Dewey 617 Autre Supported by the division of Anesthesiology, Pharmacology and Intensive Care, HUG 31 Section des sciences pharmaceutiques 17 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 false 302 Groupe Desmeules Jules (pharmacologie/toxicologie) 567 1280 Pharmaco-omiques et médecine de précision 1003 Basic & clinical pharmacology & toxicology 112 2 fb29f26c-2d03-4633-9ba4-d88361c733f3 Article (Published version) Public bcpt0112-0132.pdf 266849 application/pdf openAccess Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers	Basic & clinical pharmacology & toxicology			2013	662	428

Archive ouverte UNIGE

Staub, Christian Olivier