Abstract 9497: Dose Reduction of Ticagrelor in Ticagrelor Hyper-responders: A Pharmacokinetics and Pharmacodynamics (pkpd) Study

Abstract

Introduction: Ticagrelor has demonstrated superiority to Clopidogrel in reducing major adverse cardiovascular events, but at the cost of higher bleeding risk. However, the benefits were not replicated in the Asian trials, which demonstrated excess bleeding risk. We aimed to study the effect of Ticagrelor dose reduction in Ticagrelor hyper-responders, in addition to explore the effect of genotypes on Ticagrelor PKPD. Methods: ST-elevation myocardial infarction patients who undergone percutaneous coronary intervention and tested to be Ticagrelor hyper-responders defined as platelet reactivity of <19U based on multiple electrode aggregometry ( MEA ), were recruited. Peak and trough concentration of Ticagrelor and its active metabolite AR-C124910XX, and platelet reactivity at the corresponding time points were measured when patients were on Ticagrelor 90 mg twice daily (BD) and again when reduced to Ticagrelor 45mg BD for at least 14 days. Platelet reactivity and plasma concentrations were measured using Multiplate ® Analyzer and liquid chromatography-mass spectrometry respectively. Results: Seventeen patients were recruited and 12 were reduced to Ticagrelor 45 mg BD. The mean age of the 12 patients was 55.92 (±9.41). Their average BMI was 25.33 (±4.24), there were 11 males, and comprised of 5 Chinese, 3 Malay, 3 Indian and 1 Eurasian. Plasma concentration (geometric mean) of parent Ticagrelor and its metabolite were 2-2.6 folds (p=0.002) higher at 90 mg compared to at 45 mg [C trough_Ticagrelor 267.22 ng/mL vs 131.83 ng/mL, C trough_metabolite 158.25 ng/mL vs 62.34 ng/mL, C peak_Ticagrelor 619.89 ng/mL vs 255.57 ng/mL and C peak_metabolite 236.21 ng/mL vs 91.64 ng/mL]. The mean MEA 45mg was 23U (±8) for trough 45mg . Even after dose reduction, all patients were still at “responder” MEA levels with responder MEA defined as MEA<47U. CYP3A5*3 heterozygote was associated with higher peak 90mg and trough 90mg concentrations; p=0.037 and 0.025 respectively. Conclusions: Ticagrelor 45mg BD results in significantly lower serum levels but was still able to confer sufficient platelet inhibition. Larger studies should be conducted to correlate with clinical outcomes, and the impact of CYP3A5*3 on Ticagrelor response.