Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals

Abstract

Purpose The aim of this study was to assess age and gender effects on ticagrelor pharmacokinetics and pharmacodynamics (PK/PD). Methods Forty healthy individuals [18-45 years (young); ≥65 years (elderly); ten men, ten women per age group) received 200 mg ticagrelor. Results Ticagrelor was rapidly absorbed [time to maximum concentration (C max ) (t max ) 2.5-3.0 h], and its major active metabolite, AR-C124910XX rapidly formed (t max 3.0-3.5 h) in all groups. Ticagrelor exposure was higher in elderly vs. the young [area under the curve from time 0 to infinity (AUC 0-∞ ) 52%; C max 63% higher] and women vs. men (AUC 0-∞ 37%; C max 52% higher). Mean terminal elimination half-life was slightly longer in women vs. men but was unaffected by age. Similar results were observed for AR-C124910XX (elderly vs. young, AUC 0-∞ 48%; C max 61% higher), and in women vs. men (AUC 0-∞ 55%; C max 56% higher). Across all groups, ticagrelor produced substantial final-extent inhibition of platelet aggregation (IPA): >90% at 4 and 8 h postdose. Individuals with highest ticagrelor exposure (i.e., elderly) had the lowest IPA, indicating an age-related platelet sensitivity effect. In young individuals, platelet sensitivity was greater in men vs. women. Ticagrelor tolerability was not affected by age or gender. Conclusions Systemic exposures to ticagrelor and AR-C124910XX were higher in elderly vs. young and in women vs. men. Age-and gender-related changes in IPA were apparent, but substantial IPA was achieved in all groups.No adjustment in ticagrelor dose should be considered necessary based on age and gender.

Comparison of bioavailability and antiplatelet action of ticagrelor in patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction: A prospective, observational, single-centre study

“…Gender, age, concomitant food intake, preloading with clopidogrel or genetic effects have been reported not to affect ticagrelor absorption or its antiplatelet effect [11, 19–21]. On the other hand, AMI patients receiving morphine are at greater risk of attenuated ticagrelor bioavailability and inadequate platelet inhibition [10].…”

Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects

“…The greatest individual increase in ticagrelor exposure in our homogenous group of healthy young subjects was a more than three‐fold increase in the AUC of ticagrelor. Age, gender, drug interactions and concomitant diseases can affect platelet function, as well as the pharmacokinetics and pharmacodynamics of ticagrelor ; these individual factors may thus modify the magnitude of the grapefruit juice–ticagrelor interaction and its clinical consequences in individual patients. A further caveat is that by increasing ticagrelor exposure, grapefruit juice can prolong the recovery of platelets after ticagrelor dosing, which can be of significance when preparing for surgery , or during management of bleeding complications.…”

A New Reversible and Potent P2Y12 Receptor Antagonist (ACT-246475): Tolerability, Pharmacokinetics, and Pharmacodynamics in a First-in-Man Trial

“…A dedicated gender study in human subjects is needed to explore any differences in pharmacokinetics, as well as in pharmacodynamics, and in the pharmacokinetic-pharmacodynamic relationship. In a recent study investigating the platelet response to single doses of ticagrelor in elderly and in young females, compared to young males, the authors reported higher platelet sensitivity to treatment in young males than in female and elderly subjects [28]. The effect of various formulations and of the doubleprodrug on the pharmacokinetics of ACT-281959 and ACT-246475 had been investigated in rats and dogs and showed species differences.…”