Effect of Genetic Polymorphism Including NUP153 and SVEP1 on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects

• Published in: Clinical drug investigation Vol. 42; no. 5; pp. 447 - 458
• Main Authors: Xiang, Qian, Liu, Zhiyan, Mu, Guangyan, Xie, Qiufen, Zhang, Hanxu, Zhou, Shuang, Wang, Zining, Guo, Ninghong, Huang, Jie, Jiang, Jie, Li, Jian, Yang, Guoping, Cui, Yimin
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.05.2022; Springer Nature B.V
• Subjects: Adenosine; Adenosine diphosphate; Bioequivalence; Bioinformatics; Blood platelets; Cell Adhesion Molecules; Clinical trials; Drug development; Drug dosages; Gene loci; Genome-Wide Association Study; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - pharmacology; Ion Channels; Lectins, C-Type; Medicine; Medicine & Public Health; NCT; NCT03161002; Nuclear Pore Complex Proteins - pharmacology; Nucleotides - pharmacology; Original Research Article; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Platelet Aggregation; Platelet Aggregation Inhibitors; Poly(ADP-ribose) Polymerases - pharmacology; Polymorphism; Polymorphism, Single Nucleotide - genetics; Protein Serine-Threonine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins; Purinergic P2Y Receptor Antagonists; Stroke; Ticagrelor; Beijing China; United States > US; China
• ISSN: 1173-2563; 1179-1918; 1179-1918
• DOI: 10.1007/s40261-022-01154-6

Background and Objective The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese subjects. Methods This is a multi-center study in China, including three hospitals from Beijing, Nanchang, and Changsha. Healthy Chinese subjects aged 18–45 years with unknown genotypes were included. All subjects received a single oral dose of 90 mg of ticagrelor. Platelet aggregation and the area under the concentration–time curve for ticagrelor and its major active metabolite in plasma samples were assessed. Genome-wide association studies and candidate gene association analysis related to ticagrelor were performed. Results One hundred and seventy-five native Chinese subjects were enrolled and completed the study. According to the p value, the threshold of ticagrelor population was 6.57 × 10 −7 (0.05/76106), one single-nucleotide polymorphism chr6:17616513 of gene NUP153 ( p = 2.03 × 10 −7 ) related to the area under the concentration–time curve for plasma concentration at time zero versus the last measurable timepoint, and one single nucleotide polymorphism rs17204533 of gene SVEP1 ( p = 3.96 × 10 −7 ) related to P2Y12 reaction unit 12h of ticagrelor was identified. In addition, L1TD1, CETP, CLEC2A, CHSY1, PDZRN3, CTU2, PIEZO1, APOBEC1, SEMA6A, KAZN, and FASN polymorphisms might influence the pharmacokinetics of ticagrelor, while PARP10, TRIB1, CYP2C19, and UGT2B7 might affected its pharmacodynamics. Conclusions Genetic variation affects the pharmacokinetics and pharmacodynamics of ticagrelor in healthy individuals. The detection of NUP153, SVEP1 gene variation will be helpful for pharmacodynamic prediction and evaluation, and the regulation of these genes may be the target of new drug development. Further studies are required to confirm the results and explore whether these single-nucleotide polymorphisms are associated only with platelet activity or also with cardiovascular events and all-cause mortality. Clinical Trial Registration NCT03161002.