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 (Cmax) and area under the plasma concentration-time curve from Time 0 to infinity (AUC0-∞) were lose 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 (t1/2), and time to maximal plasma concentrations (tmax) for tolbutamide and its metabolite were unaffected by ticagrelor coadministration. Tolbutamide had no effect on the Cmax, area under the concentration curve over the 2-hour dosing interval (AUC0-τ), t1/2 or tmax of either ticagrelor or AR-C124910XX. Coadministration 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.
RCT Entities:
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 (Cmax) and area under the plasma concentration-time curve from Time 0 to infinity (AUC0-∞) were lose 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 (t1/2), and time to maximal plasma concentrations (tmax) for tolbutamide and its metabolite were unaffected by ticagrelor coadministration. Tolbutamide had no effect on the Cmax, area under the concentration curve over the 2-hour dosing interval (AUC0-τ), t1/2 or tmax of either ticagrelor or AR-C124910XX. Coadministration 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.