Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects.
British journal of clinical pharmacology | 7 Nov 2012
MT Holmberg, A Tornio, L Joutsi-Korhonen, M Neuvonen, PJ Neuvonen, R Lassila, M Niemi and JT Backman
AIM: This study examined the effects of grapefruit juice on the new P2Y(12) inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein. METHODS: In a randomized crossover study, ten healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for four days. On day three, they ingested a single 90-mg dose of ticagrelor. RESULTS: Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (C(max) ) to 165% (95% confidence interval, 147-184%) and area under the concentration-time curve (AUC(0-∞) ) to 221% of control (95% confidence interval, 200-245%). The C(max) and AUC(0-34h) (P < 0.05) but not the AUC(0-∞) of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity. CONCLUSIONS: Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice-ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.
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