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 (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.

Drug Interactions and Antiretroviral Drug Monitoring

“…This is due to decreased prasugrel activation through RTV inhibition of CYP3A4. 46 Cobicistat may have a similar effect on prasugrel. 43 Ticagrelor does not require activation, but is metabolized by and inhibits CYP3A4, 47 thereby increasing the risk of excess anticoagulation if used in conjunction with other CYP3A4 inhibitors.…”

Automated Direct Extraction and Analysis of Dried Blood Spots Employing On-Line SPE High-Resolution Accurate Mass Bioanalysis

“…The concept of dried blood spot (DBS) for the collection and analysis of samples may provide opportunities towards these benefits and has received considerable interest from the pharmaceutical industry for qualitative and quantitative analysis at various stages of drug discovery and development, including nonclinical studies and clinical trials [2][3][4][5].…”

Managing drug interactions in HIV-infected adults with comorbid illness

“…In a study involving healthy volunteers, inhibition of CYP3A4 by ritonavir reduced the area under the curve for the active metabolite of prasugrel by 40%. 36 For patients receiving protease inhibitors or cobicistat, use of clopidogrel may be preferable, as a clinically important interaction with the latter would not be expected. However, for HIV-infected patients receiving the NNRTI efavirenz or etravirine, prasugrel or ticagrelor may be a safer option because of a lower risk of interactions.…”