Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects

Ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, is predominantly metabolized by cytochrome P450 3A and both the parent compound and its active metabolite AR-C124910XX are substrates of P-glycoprotein. Rifampicin was used to assess the effects of CYP3A and P-glycoprotein induction on the single-dose pharmacokinetics and pharmacodynamics of ticagrelor. Healthy volunteers received a single 180 mg oral dose of ticagrelor on days 1 and 15, and a once-daily 600 mg dose of rifampicin on days 4-17. Ticagrelor and AR-C124910XX plasma concentrations were quantified for pharmacokinetic analysis (n = 14); inhibition of platelet aggregation (IPA) was also assessed (n = 14). Compared with administration of ticagrelor alone, co-administration of ticagrelor and rifampicin significantly decreased the maximum plasma concentration (C-max) of ticagrelor from 1091 to 297.8 ng/ml, area under the plasma concentration-time curve from time zero to infinity (AUC) of ticagrelor from 6225 to 864.0 ng.h/ml, and also decreased plasma half-life of ticagrelor from 8.4 to 2.8 h; reductions of 73 %, 86 % and 67 % respectively. With rifampicin, AR-C124910XX C-max was unaffected, AUC was significantly decreased by 46 %, and metabolite to parent ratio for AUC increased fourfold. Although maximal IPA was unaffected, offset of ticagrelor-mediated IPA was more rapid in the presence of rifampicin; a significant reduction (27 %) in the area under the effect curve between 0 and 24 h was observed following co-administration with rifampicin. Co-administration with rifampicin reduced ticagrelor exposure and resulted in a more rapid offset of ticagrelor-mediated IPA. Co-administration of strong CYP3A/P-glycoprotein inducers with ticagrelor should be discouraged.