Pharmacokinetic interaction between prasugrel and ritonavir in healthy volunteers.
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.
Clinical Pharmacology and Toxicology Service, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
Virginie
V
Ancrenaz
Julien
J
Déglon
Caroline
C
Samer
Christian
C
Staub
Pierre
P
Dayer
Youssef
Y
Daali
Jules
J
Desmeules
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D008874:Midazolam / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics*; D000068799:Prasugrel Hydrochloride; D019438:Ritonavir / Q000494:pharmacology*; D013876:Thiophenes / Q000493:pharmacokinetics*; D013997:Time Factors; D055815:Young Adult
D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D010879:Piperazines; D013876:Thiophenes; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000068799:Prasugrel Hydrochloride; D019438:Ritonavir; D008874:Midazolam