Impact of Boosted Antiretroviral Therapy on the Pharmacokinetics and Efficacy of Clopidogrel and Prasugrel Active Metabolites

• Published in: Clinical pharmacokinetics Vol. 57; no. 10; pp. 1347 - 1354
• Main Authors: Marsousi, Niloufar, Daali, Youssef, Fontana, Pierre, Reny, Jean-Luc, Ancrenaz-Sirot, Virginie, Calmy, Alexandra, Rudaz, Serge, Desmeules, Jules Alexandre, Samer, Caroline Flora
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2018; Springer Nature B.V
• Subjects: Acute coronary syndromes; Antiretroviral drugs; Clinical medicine; Cytochrome; Drug dosages; Drug therapy; Glycoproteins; HIV; Human immunodeficiency virus; Internal Medicine; Medicine; Medicine & Public Health; Metabolism; Metabolites; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-018-0637-6

Background and objectives Prasugrel and clopidogrel are inhibitors of the ADP-P 2 Y 12 platelet receptor used in acute coronary syndrome patients. They require bioactivation via isoenzymes such as cytochrome P450 (CYP) 3A4, CYP2C19 and CYP2B6. Ritonavir and cobicistat are potent CYP3A inhibitors, prescribed as pharmacokinetic (PK) enhancers in the treatment of human immunodeficiency virus (HIV) infection. Methods In this study, the impact of boosted antiretroviral therapies (ARTs) on the PK of clopidogrel and prasugrel active metabolites (AMs), and on the efficacy of prasugrel and clopidogrel, were evaluated in a randomized crossover clinical trial. Results A significantly lower exposure to clopidogrel AM [3.2-fold lower area under the concentration–time curve (AUC) and maximum plasma concentration ( C max )] and prasugrel AM (2.1-fold and 1.7-fold lower AUC and C max ) were demonstrated in HIV-infected patients treated with boosted ARTs compared with healthy controls; however, a differential impact was observed on platelet inhibition between clopidogrel and prasugrel. Clopidogrel 300 mg induced adequate (although modest) platelet inhibition in all healthy subjects, while platelet inhibition was insufficient in 44% of HIV patients. On the contrary, prasugrel 60 mg induced a potent platelet inhibition in both healthy and HIV-infected subjects. Conclusion Prasugrel appears to remain an adequate antiplatelet agent in HIV-infected patients and could be preferred to clopidogrel in this context, regardless of the metabolic interaction and inhibition of its bioactivation pathways.