Evaluation of the pharmacokinetic interaction between ticagrelor and tolbutamide, a cytochrome P450 2C9 substrate, in healthy volunteers

Objectives: To assess the effect of ticagrelor on the pharmacokinetics of tolbutamide (a CYP2C9 substrate), and the effect of tolbutamide on ticagrelor pharmacokinetics. Methods: In this randomized, double-blind, two-period, crossover study, 23 healthy volunteers received either placebo or ticagrelor 180 mg twice daily (b.i.d.) for 9 days, with a single open-label oral dose of tolbutamide 500 mg on Day 5. After washout (14 days), volunteers received the alternate treatment. Plasma concentrations of tolbutamide, 4-hydroxytolbutamide, ticagrelor, and AR-C124910XX were determined for pharmacokinetic analyses. Results: Ticagrelor had no effect on tolbutamide or 4-hydroxytolbutamide pharmacokinetic parameters. The geometric least square mean ratios for maximum plasma concentration (C-max) and area under the plasma concentration-time curve from Time 0 to infinity (AUC(0-infinity)) were close to unity, and the 90% confidence intervals (CI) were within the range 0.80 - 1.25 for both tolbutamide and 4-hydroxytolbutamide. The terminal elimination half-life (t(1/2)), and time to maximal plasma concentrations (t(max)) for tolbutamide and its metabolite were unaffected by ticagrelor coadministration. Tolbutamide had no effect on the C-max, area under the concentration curve over the 12-hour dosing interval (AUC(0-tau)), t(1/2) or t(max) of either ticagrelor or AR-C124910XX. Co-administration of ticagrelor and tolbutamide was well tolerated. Conclusions: These results suggest that ticagrelor does not affect tolbutamide metabolism and is therefore unlikely to affect CYP2C9-mediated metabolism of drugs.