Pharmacokinetic Interaction Between Prasugrel and Ritonavir in Healthy Volunteers

• Published in: Basic & clinical pharmacology & toxicology Vol. 112; no. 2; pp. 132 - 137
• Main Authors: Ancrenaz, Virginie, Déglon, Julien, Samer, Caroline, Staub, Christian, Dayer, Pierre, Daali, Youssef, Desmeules, Jules
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell 01-02-2013; Wiley Subscription Services, Inc; Blackwell Publishing Ltd
• Subjects: Adult; Area Under Curve; Biological and medical sciences; Blood; bupropion; Cross-Over Studies; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P450; Data processing; Drug Interactions; Flurbiprofen; Half-Life; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - pharmacology; Human immunodeficiency virus; Humans; Male; Medical sciences; Metabolites; midazolam; Midazolam - metabolism; Omeprazole; Original; Pharmacokinetics; Pharmacology. Drug treatments; Piperazines - pharmacokinetics; Prasugrel Hydrochloride; Ritonavir; Ritonavir - pharmacology; Sampling; Thiophenes - pharmacokinetics; Time Factors; Young Adult; Human; Antiretroviral agent; Healthy subject; Enzyme; Ritonavir; Interaction; Enzyme inhibitor; Antiplatelet agent; Prasugrel; Peptidases; Antithrombotic agent; Hydrolases; Antiviral; Pharmacokinetics; Protease inhibitor
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/j.1742-7843.2012.00932.x

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 (Cmax, t1/2, tmax, AUC0–6 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 Cmax 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 t1/2 and tmax 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.