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Pharmacokinetic Interaction Between Prasugrel and Ritonavir in Healthy Volunteers
Author(s) -
Ancrenaz Virginie,
Déglon Julien,
Samer Caroline,
Staub Christian,
Dayer Pierre,
Daali Youssef,
Desmeules Jules
Publication year - 2013
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2012.00932.x
Subject(s) - prasugrel , ritonavir , pharmacokinetics , pharmacology , drug interaction , active metabolite , medicine , chemistry , clopidogrel , aspirin , human immunodeficiency virus (hiv) , family medicine , antiretroviral therapy , viral load
The new anti‐aggregating agent prasugrel is bioactivated by cytochromes P 450 ( CYP ) 3 A and 2 B 6. Ritonavir is a potent CYP 3 A inhibitor and was shown in vitro as a CYP 2 B 6 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 CYP 2 B 6, 2 C 9, 2 C 19 and 3 A 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 CYP 3 A 4, whereas omeprazole, flurbiprofen and bupropion MR were not affected. These data demonstrate that ritonavir is able to block prasugrel CYP 3 A 4 bioactivation. This CYP ‐mediated drug–drug interaction might lead to a significant reduction of prasugrel efficacy in HIV ‐infected patients with acute coronary syndrome.