Abstract
Background: Ticagrelor belongs to a new class of P2Y12 receptor inhibitor that has been widely used for antiplatelet therapy. This study aimed to explore the effect of single nucleotide polymorphisms (SNPs) in metabolic enzymes, transporters, and other relevant variants on the pharmacokinetics (PK) of ticagrelor and its active metabolite, AR-C124910XX. Methods: The study population comprised 68 healthy Chinese volunteers who were enrolled in a ticagrelor bioequivalence clinical trial. The PK profile of ticagrelor was evaluated after orally administering a single 90-mg dose of ticagrelor in tablet form. The plasma concentrations of ticagrelor and AR-C124910XX were determined through liquid chromatography–tandem mass spectrometry. Plasma DNA samples were used to explore the effect of gene polymorphisms on the PK of ticagrelor and AR-C124910XX with whole-exome sequencing. Results: Female participants had a higher maximum plasma concentration/weight ratio (C max/W; p < 0.001) and a shorter half-life (T 1/2; p < 0.05) for ticagrelor than their male counterparts. In addition, a higher area under the curve/weight ratio (AUC/W; p < 0.001), and longer T 1/2 (p < 0.001) and time to reach the maximum plasma concentration (T max; p < 0.001), as well as a lower apparent drug clearance (CL/F; p < 0.001), were observed among healthy volunteers in the fed trial compared to those enrolled in the fasting trial. For AR-C124910XX, higher C max/W (p < 0.001) and AUC/W (p < 0.001) but lower CL/F (p < 0.001) and apparent volume of distribution (V d/F; p < 0.001) were observed among female participants. Healthy volunteers enrolled in the fasting trial exhibited higher C max/W (p < 0.001) and AUC/W (p < 0.01), shorter T max (p < 0.001), and lower CL/F (p < 0.001) and V d/F (p < 0.001) than those enrolled in the fed trial. Upon confirmation through multivariate analysis, the CYP4F2 rs2074900 A/A carriers were associated with higher C max/W and AUC/W and lower CL/F and V d/F than the CYP4F2 rs2074900 A/G and G/G carriers. Conclusion: This study is the first to show that the CYP4F2 rs2074900 SNP had a remarkable effect on ticagrelor PK, which is significant since it adds to the limited pharmacogenetic information on ticagrelor.
Highlights
Cardiovascular diseases are the leading cause of mortality worldwide, and up to 30% of patients die of acute coronary events every year (Rodrigues et al, 2020)
Higher Cmax/W (p < 0.001) and area under the curve (AUC)/W (p < 0.01) and a shorter the maximum plasma concentration (Tmax) (p < 0.001) and lower CL/F (p < 0.001) and Vd/F (p < 0.001) were observed in healthy volunteers enrolled in the fasting trial than those enrolled in the fed trial
Owing to the East Asian paradox, East Asian patients with acute coronary syndrome (ACS) are at a higher risk of major bleeding than ischemic risk compared to Caucasians; a unique antiplatelet strategy needs to be urgently established for East Asian individuals on the basis of reliable clinical and experimental evidence (Kim et al, 2021)
Summary
Cardiovascular diseases are the leading cause of mortality worldwide, and up to 30% of patients die of acute coronary events every year (Rodrigues et al, 2020). Guidelines of the American College of Cardiology/American Heart Association recommend the administration of dual antiplatelet therapy (aspirin + a platelet P2Y12 inhibitor) to prevent atherothrombotic complications for 12 months (Capodanno et al, 2018). The TICO (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus-Eluting Stent for Acute Coronary Syndrome) clinical trial reported that ticagrelor monotherapy after 3 months of dual antiplatelet therapy significantly reduced the incidence of composite outcomes of major bleeding and cardiovascular events at 12 months for patients with ACS treated with drug-eluting stents (Kim et al, 2019; Kim et al, 2020). The guidelines of the European Society of Cardiology have recommended the administration of ticagrelor therapy for patients at moderate to high ischemic risk with a class of recommendation Ι, level of evidence B (Rodriguez and Mahaffey, 2016). This study aimed to explore the effect of single nucleotide polymorphisms (SNPs) in metabolic enzymes, transporters, and other relevant variants on the pharmacokinetics (PK) of ticagrelor and its active metabolite, ARC124910XX
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