Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers.

Abstract

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.

• Authors: Virginie Ancrenaz, Julien Déglon, Caroline Samer, Christian Staub, Pierre Dayer, Youssef Daali, Jules Desmeules
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 112 Issue 2 Pg. 132-7 (Feb 2013) ISSN: 1742-7843 [Electronic] England
• PMID: 22900583 (Publication Type: Controlled Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.

Chemical References

• Cytochrome P-450 CYP3A Inhibitors
• HIV Protease Inhibitors
• Piperazines
• Thiophenes
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Prasugrel Hydrochloride
• Ritonavir
• Midazolam

Topics

• Adult
• Area Under Curve
• Cross-Over Studies
• Cytochrome P-450 CYP3A (metabolism)
• Cytochrome P-450 CYP3A Inhibitors
• Drug Interactions
• HIV Protease Inhibitors (pharmacokinetics, pharmacology)
• Half-Life
• Humans
• Male
• Midazolam (metabolism)
• Piperazines (pharmacokinetics)
• Prasugrel Hydrochloride
• Ritonavir (pharmacology)
• Thiophenes (pharmacokinetics)
• Time Factors
• Young Adult