A Phase 1 Study of Novel Antiplatelet Agent to Overcome Pharmacogenomic Limitations of Clopidogrel

Abstract

AbstractBackgroundClopidogrel 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.MethodsTwo 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.ResultsOverall 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.ConclusionAT-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. CTRI Registration: CTRI/2021/03/032206Clinical PerspectivesAT-10 (2-oxo-Clopidogrel) is a novel thienopyridine P2Y12 inhibitor under clinical development in India.It is a Clopidogrel derivative that is metabolically converted to produce the active thiol metabolite similar to Clopidogrel.The response to AT-10 was found unaffected by genetic CYP2C19 polymorphisms to the extent of its influence in Clopidogrel, thus eliminating the need for characterization of Clopidogrel responsiveness and thereby maintaining effectiveness in all patients, including those patients who are identified as CYP2C19 poor and intermediate metabolizers.Further studies are required to investigate the influence of CYP2C19 functional polymorphisms on the response to AT-10 dose in diverse clinical settings, and especially on the risk of recurrent thrombotic events during AT-10 treatment as compared to Clopidogrel therapy.