Identification of genetic biomarkers associated with pharmacokinetics and pharmacodynamics of apixaban in Chinese healthy volunteers

ABSTRACT

Background

Apixaban is a superior direct oral anticoagulant exihibiting interindividual variability in concentration and response in the real world. The present study aimed to identify genetic biomarkers associated with pharmacokinetics (PK) and pharmacodynamics (PD) of apixaban in healthy Chinese subjects.

Methods

This multicenter study included 181 healthy Chinese adults taking a single dose of 2.5 mg or 5 mg apixaban and assessed their PK and PD parameters. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed using the Affymetrix Axiom CBC_PMRA Array. Candidate gene association analysis and genome-wide association study were conducted to identify genes with a predictive value for PK and PD parameters of apixaban.

Results

Several ABCG2 variants were associated with C_max and AUC_0-t of apixaban (p < 6.12 × 10⁻⁵) and also presented significant differences of anti-Xa_3h activity and dPT_3h according to different ABCG2 genotypes (p < 0.05). Besides, ABLIM2 variants were found to be associated with PK characteristics and F13A1 and C3 variants were associated with PD characteristics of apixaban (p < 9.46 × 10⁻⁸).

Conclusion

ABCG2 variants were found to be ideal genetic biomarkers for both PK and PD characteristics of apixaban. ABLIM2, F13A1 and C3 were identified as potential candidate genes associated with inter-individual variability of apixaban. This study was registered on ClinicalTrials.gov NCT03259399.

KEYWORDS:

• Apixaban
• candidate gene
• genome-wide association analysis
• pharmacokinetics
• pharmacodynamics

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2023.2184344.

Additional information

Funding

This work was supported by grants from the National Key R&D Program of China [grant number 2016YFC0904900], National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ [grant number 2017ZX09101001], National Natural Science Foundation of China [grant numbers 81872940, 81973395, and 82073935], and Beijing Municipal Commission of Science and Technology of China Pharmaceutical Innovation Cultivation and Industry Support Platform Capacity Construction Project [grant number Z191100007619038].