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.

Fig. 1

Metabolic pathways of the anti-aggregating agent prasugrel [8].

Fig. 2

Mean (±S.D.) whole blood concentrations for prasugrel's active metabolite in dried blood spots after prasugrel alone (Δ) or prasugrel with ritonavir (•). Values are shown as the mean ± S.D.

Fig. 3

Effect of ritonavir on individual (A) AUC_{0–6 hr} or (B) C_max of the prasugrel active metabolite after administration of 10 mg prasugrel alone or 10 mg prasugrel with 100 mg ritonavir. *p < 0.05, **p ≤ 0.005.

Fig. 4

Effect of ritonavir on individual metabolic ratios of (A) midazolam, (B) flurbiprofen, (C) omeprazole and (D) bupropion after administration of 10 mg prasugrel or 10 mg prasugrel with 100 mg ritonavir. *p < 0.05, **p ≤ 0.005.