Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers

Abstract

ObjectivesTwo open-label, two-period, crossover studies in healthy volunteers were designed to determine the pharmacokinetic interactions between ticagrelor, a P2Y12 receptor antagonist, and a moderate (diltiazem) and a strong (ketoconazole) cytochrome P450 (CYP) 3A inhibitor.MethodsSeventeen volunteers received diltiazem (240 mg once daily) for 14 days. In the second study, ketoconazole (n = 14) 200 mg twice daily was given for 10 days. A single oral 90-mg ticagrelor dose was administered on day 8 (diltiazem) or day 4 (ketoconazole). In each study, volunteers received a single 90-mg oral dose of ticagrelor before or after washout (≥14 days). Pharmacokinetic parameters for ticagrelor, AR-C124910XX (primary metabolite), diltiazem, and ketoconazole were assessed.ResultsCompared with ticagrelor alone, diltiazem co-administration significantly increased the mean maximum concentration (Cmax) and mean area under the plasma concentration–time curve (AUC) for ticagrelor by 69% and 174%, respectively. Diltiazem co-administration reduced Cmax by 38% but had no significant effect on AUC for AR-C124910XX. Cmax and AUC for ticagrelor were increased by 135% and 632%, respectively, by ketoconazole co-administration, whereas these parameters were reduced by 89% and 56%, respectively, for AR-C124910XX. Diltiazem and ketoconazole pharmacokinetic parameters were not significantly affected by the presence of ticagrelor.ConclusionsThese results suggest that ticagrelor can be co-administered with moderate CYP3A inhibitors. However, co-administration of strong CYP3A inhibitors with ticagrelor is not recommended.

Ticagrelor: Pharmacokinetics, Pharmacodynamics, Clinical Efficacy, and Safety

“…For example, concomitant administration of ketoconazole with ticagrelor increased the ticagrelor C max 2.4-fold and the area under the concentration-time curve (AUC) 7.3-fold. 53 Moderate CYP3A4 inhibitors have a proportional effect on ticagrelor exposure and are not contraindicated. For example, diltiazem increased the ticagrelor C max by 69%, and the AUC was increased 2.7-fold.…”

“…For example, diltiazem increased the ticagrelor C max by 69%, and the AUC was increased 2.7-fold. 53 Conversely, potent inducers of CYP3A4 may decrease exposure to and hence reduce the efficacy of ticagrelor. The combined use of potent CYP3A4 inducers with ticagrelor should be avoided based on a healthy volunteer study in which coadministration of rifampin decreased the ticagrelor C max and AUC by 73% and 86%, respectively (Table 4 ).…”

Does morphine administration affect ticagrelor conversion to its active metabolite in patients with acute myocardial infarction? A sub-analysis of the randomized, double-blind, placebo- -controlled IMPRESSION trial

“…Strong CYP3A4 inhibitors (e.g. ketoconazole) act conversely [19]. Most opioids are metabolized through CYP-mediated oxidation, including CYP3A4, and have significant potential for drug-drug interactions [20].…”

Ticagrelor Increases SIRT1 and HES1 mRNA Levels in Peripheral Blood Cells from Patients with Stable Coronary Artery Disease and Chronic Obstructive Pulmonary Disease

“…Severity of diseases, co-morbidities, and pharmacological treatment can determine differences in gene expression. Furthermore, drug interaction may modulate ticagrelor concentration and therefore effectiveness of the treatment [52]. To identify possible associations between disease severity, comorbidity or drug treatment, we performed correlation analyses between these variables and changes in SIRT1 or HES1 after a 1-month treatment.…”