Background: Clopidogrel is the most commonly prescribed thienopyridine as part of dual antiplatelet therapy for the treatment of cardiovascular diseases. However, Clopidogrel responsiveness shows variability based on CYP2C19 polymorphism. Therefore, we planned a study with an objective of evaluating safety, tolerability, pharmacodynamics and pharmacokinetics of a novel thienopyridine antiplatelet agent AT-10 in healthy Indian subjects in comparison with standard dosage regimen of Clopidogrel based on their CYP2C19 genotyping. Methods: Two CYP2C19 genotype-based groups were identified i.e., Poor Metabolizer and Extensive Metabolizers with 20 subjects in each group (N=40) for participating in a randomized, two period, cross-over study. Each study period lasted 6 days including administration of loading and maintenance doses of AT-10 (40mg/10mg) or Clopidogrel (300mg/75mg). The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 6 at several time intervals. Results: Overall result of pharmacodynamic parameters showed that, mean % Inhibition of Platelet Aggregation between AT-10 and Clopidogrel in all subjects at post-dose 6hr (loading dose) (AT-10: Clopidogrel; 73.30% vs. 18.53%) and post-dose 6 hr on Day 6 (maintenance dose) (AT-10: Clopidogrel; 83.41% vs. 51.19 %) obtained from the AT-10 group was significantly higher than the Clopidogrel group. Further, %inhibition of platelet aggregation from AT-10 treatment in poor metabolizer group was significantly higher than the Clopidogrel treatments in extensive metabolizer group. Overall pharmacokinetic comparison in all subjects indicates that AT-10 gives greater exposure to active Metabolite MP-H4 than Clopidogrel. Conclusion: AT-10 may emerge as a promising anti-platelet drug and can be further developed in clinical studies for the unmet medical needs of cardiovascular diseases.

The authors have declared no competing interest.

CTRI/2021/03/032206

This work was funded by Ipca Laboratories Limited.

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