prasugrel-hydrochloride and HIV-Infections

Prasugrel and clopidogrel are inhibitors of the ADP-P. 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.. A significantly lower exposure to clopidogrel AM [3.2-fold lower area under the concentration-time curve (AUC) and maximum plasma concentration (C. 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.

Topics: Adult; Aged; Anti-Retroviral Agents; Area Under Curve; Blood Platelets; Clopidogrel; Cross-Over Studies; Drug Interactions; HIV Infections; Humans; Male; Middle Aged; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12

To explore platelet reactivity on dual antiplatelet therapy (DAPT) of acute coronary syndrome (ACS) patients infected with HIV.. Acute coronary syndrome patients infected with HIV (n = 80) were matched to ACS patients without HIV (n = 160) on age, sex, diabetes, and DAPT (aspirin 100%, clopidogrel 68%, prasugrel 31%, ticagrelor 1%). Platelet reactivity was evaluated after ACS (>30 days) by measuring residual platelet aggregation (RPA) to aspirin and to P2Y12 inhibitors with light transmission aggregometry (LTA), VerifyNow aspirin assay (ARU), and P2Y12 assay (PRU) and with the VASP platelet reactivity index (VASP-PRI). Proportion of patients with high residual platelet reactivity (HPR) was evaluated. HIV-infected ACS patients had higher levels of platelet reactivity in response to P2Y12 inhibitors (RPA: 23.8 ± 2.7% vs. 15.3 ± 1.3%; P = 0.001; PRU: 132 ± 10 vs. 107.4 ± 6.6; P = 0.04; and VASP-PRI: 45.2 ± 2.6% vs. 32.0 ± 2.0%; P < 0.001) and to aspirin (RPA: 3.6 ± 1.5% vs. 0.4 ± 0.1%; P = 0.004 and ARU: 442 ± 11 vs. 407 ± 5; P = 0.002) compared with non-HIV. HIV-infection was independently associated with increased platelet reactivity regardless of the test used (RPA: P = 0.005; PRU: P < 0.001 and VASP-PRI: P < 0.001) and a higher proportion of HPR (OR = 7.6; P < 0.001; OR = 2.06; P = 0.06; OR = 2.91; P = 0.004, respectively) in response to P2Y12 inhibitors. Similar results were found with aspirin. Protease inhibitors use was associated with increased platelet reactivity and higher rate of HPR.. Acute coronary syndrome patients infected with HIV have increased levels of platelet reactivity and higher prevalence of HPR to P2Y12 inhibitors and aspirin than non-HIV patients. These results could provide potential explanations for the observed increase risk of recurrent ischemic events in the HIV-infected population.

Topics: Acute Coronary Syndrome; Adenosine; Anti-HIV Agents; Aspirin; Blood Platelets; Clopidogrel; Cross-Sectional Studies; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Recurrence; Risk Factors; Ticagrelor; Ticlopidine

Prasugrel is an antiplatelet prodrug used in patients with acute coronary syndrome. Prasugrel is mainly bioactivated by cytochromes P450 3A4/5 and CYP2B6. HIV patients are at risk of cardiovascular disease, and the protease inhibitor ritonavir is a potent inhibitor of these 2 CYPs. The aim of this in vitro study was to determine the impact of ritonavir in prasugrel metabolism. Human liver microsomes (HLMs) and recombinant microsomes were used to identify the enzymes responsible for the bioactivation of prasugrel. Prasugrel concentrations of 5 to 200 μM were used for Km determination. Inhibition by ritonavir was characterized using HLMs at concentrations of 0.1 to 30 μM. Prasugrel active metabolite determination was performed with a validated liquid chromatography-mass spectrometry method. Using recombinant microsomes, prasugrel biotransformation was mainly performed by CYP2B6, CYP2D6, CYP2C19, CYP3A4, and CYP3A5. With specific inhibitors of CYP3A, CYP2B6, CYP2D6, CYP2C9, and CYP2C19, active metabolite production was decreased by 38% ± 15% with 4-(4-chlorobenzyl)pyridine (CYP2B6 inhibitor) and by 45 ± 16% with ketoconazole (CYP3A inhibitor). The Km value for prasugrel metabolism in HLMs was determined to be 92.5 μM. Ritonavir at 0.1 to 30 μM was shown to be a potent dose-dependent inhibitor of prasugrel. In this in-vitro study, we found a potent inhibition of prasugrel bioactivation by ritonavir compared to the specific inhibitors of CYP3A and CYP2B6 due to the simultaneous inhibition of CYP2B6 and CYP3A by ritonavir. This finding suggests a potential significant drug-drug interaction between these two drugs.

Topics: Bupropion; Dose-Response Relationship, Drug; Down-Regulation; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; In Vitro Techniques; Inactivation, Metabolic; Metabolic Networks and Pathways; Microsomes, Liver; Models, Biological; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Ritonavir; Thiophenes

Topics: HIV Infections; Humans; Piperazines; Prasugrel Hydrochloride; Ritonavir; Thiophenes