Pharmacokinetic Interaction Between Prasugrel and Ritonavir in Healthy Volunteers

Virginie Ancrenaz,Caroline Samer,Pierre Dayer,Christian Staub,Jules Desmeules,Youssef Daali,Julien Déglon

doi:10.1111/j.1742-7843.2012.00932.x

Virginie Ancrenaz, Caroline Samer + Show 5 more

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https://doi.org/10.1111/j.1742-7843.2012.00932.x

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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 (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.

Highlights

IntroductionThe active metabolite of prasugrel (prasugrel AM) is an irreversible inhibitor of ADP-P2Y12 platelet receptors, explaining the anti-aggregating effect of prasugrel
Prasugrel is a recently commercialized thienopyridine antiplatelet agent used to prevent atherothrombotic events in patients with acute coronary syndrome who are undergoing percutaneous coronary intervention [1].The active metabolite of prasugrel is an irreversible inhibitor of ADP-P2Y12 platelet receptors, explaining the anti-aggregating effect of prasugrel
This study shows that prasugrel pharmacokinetics is significantly altered by ritonavir

Summary

Introduction

The active metabolite of prasugrel (prasugrel AM) is an irreversible inhibitor of ADP-P2Y12 platelet receptors, explaining the anti-aggregating effect of prasugrel This pro-drug is rapidly hydrolysed by carboxylesterases into a thiolactone intermediate metabolite that is transformed by cytochromes P450 (CYP) into its pharmacologically active metabolite There was no change in prasugrel AM formation or the inhibition of platelet aggregation when prasugrel was administered with ketoconazole (a CYP3A inhibitor), atorvastatin (a CYP3A substrate) or rifampicin (a CYP3A inducer) [5–7]. Ritonavir was a potent inhibitor of prasugrel bioactivation in human liver microsomes, raising the possibility of a pharmacokinetic drug–drug interaction between ritonavir and prasugrel in vivo [8]. Such an interaction could reduce the efficacy of prasugrel. In vivo experiments are lacking to confirm these in vitro data in human beings

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