Abstract
Objectives:Two 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.Methods:Seventeen 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.Results:Compared 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.Conclusions:These results suggest that ticagrelor can be co-administered with moderate CYP3A inhibitors. However, co-administration of strong CYP3A inhibitors with ticagrelor is not recommended.
Highlights
Ticagrelor is an oral P2Y12 receptor antagonist that inhibits adenosine diphosphate-induced platelet aggregation[1]
Cmax and area under the plasma concentration–time curve (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
Ot thor lay, v Conclusions: N u p These results suggest that ticagrelor can be co-administered with moderate CYP3A inhibitors
Summary
Ticagrelor is an oral P2Y12 receptor antagonist that inhibits adenosine diphosphate-induced platelet aggregation[1]. Updated European guidelines recommend ticagrelor combined with aspirin as one of several antiplatelet therapies for managing. Updated European guidelines gave ticagrelor a Class I recommendation for patients presenting with persistent ST-segment elevation[6]. Ticagrelor is a directacting antiplatelet agent, it is metabolized to at least ten metabolites[13]. The major metabolite, AR-C124910XX, which is present at approximately 30–40% of the levels of ticagrelor[13,14,15,16,17], is approximately equipotent in inhibiting platelet aggregation (AstraZeneca, data on file). Experiments with human liver microsomes demonstrated that ticagrelor is principally metabolized by CYP3A18
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