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

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Abstract

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 unit12h 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.

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Author notes

  1. Qian Xiang and Zhiyan Liu contributed equally as first authors.

Authors and Affiliations

  1. Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China

    Qian Xiang, Zhiyan Liu, Guangyan Mu, Qiufen Xie, Hanxu Zhang, Shuang Zhou, Zining Wang & Yimin Cui

  2. School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China

    Hanxu Zhang & Yimin Cui

  3. Center of Clinical Pharmacology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China

    Ninghong Guo & Jian Li

  4. Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China

    Jie Huang & Guoping Yang

  5. Department of Cardiology, Peking University First Hospital, Beijing, China

    Jie Jiang

  6. Institute of Clinical Pharmacology, Peking University, Beijing, China

    Yimin Cui

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  1. Qian Xiang
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Corresponding author

Correspondence to Yimin Cui.

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Funding

This study was supported by Grants from the National Key R&D Program of China (2016YFC0904900), National Natural Science Foundation of China (81872940, 81973395 and 82073935), and Beijing Municipal Commission of Science and Technology of China Pharmaceutical Innovation Cultivation and Industry Support Platform Capacity Construction Project (Z191100007619038).

Conflict of interest

We declare no competing interests.

Ethics approval

The protocol was approved by an independent ethics committee and the Institutional Review Board of Peking University First Hospital and all participating research sub-central hospitals. The trial registration number is NCT03161002.

Consent to participate

All subjects were enrolled in this study after signing the informed consent.

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Not applicable.

Availability of data and material

All data related to the study have been shown in the article, and other relevant data can be communicated with the author.

Code availability

Not applicable.

Authors′ Contribution

(1) Conception and design: Yimin Cui, Guoping Yang, Ninghong Guo, Jie Huang, Jie Jiang and Jian Li; (2) Provision of study materials or patients: Qian Xiang, Zhiyan Liu, Guangyan Mu, Qiufen Xie, Hanxu Zhang and Shuang Zhou; (3) Collection and assembly of data: Zhiyan Liu and Zining Wang; (4) Data analysis and interpretation: Zhiyan Liu, Qiufen Xie, Hanxu Zhang and Qian Xiang; (5) Manuscript writing and Final approval of manuscript: All authors.

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Xiang, Q., Liu, Z., Mu, G. et al. Effect of Genetic Polymorphism Including NUP153 and SVEP1 on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects. Clin Drug Investig 42, 447–458 (2022). https://doi.org/10.1007/s40261-022-01154-6

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  • DOI: https://doi.org/10.1007/s40261-022-01154-6

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