Abstract
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. CTRI Registration: CTRI/2021/03/032206
Clinical Perspectives
AT-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.
Competing Interest Statement
The authors have declared no competing interest.
Clinical Trial
CTRI/2021/03/032206
Funding Statement
This work was funded by Ipca Laboratories Limited.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
It was approved by Sangini Hospital Ethics Committee and Indian Regulatory Authority [Central Drug Standard Control Organization (CDSCO)]. It was registered on Clinical Trials Registry India with registration number CTRI/2021/03/032206 [Registered on: 23/03/2021].
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Data Availability
No, we cannot provide data for privacy reasons.
Abbreviations
- ACS
- Acute Coronary Syndrome
- ADP
- Adenosine Diphosphate
- AUC
- Area under the curve
- BMI
- Body Mass Index
- CAD
- Coronary Artery Disease
- CDSCO
- Central Drug Standard Control Organization
- CES-1
- Carboxylesterase-1
- CVD
- Cardiovascular Disease
- CYP
- Cytochrome P
- DES
- Drug Eluting Stent
- EM
- Extensive Metabolizers
- IM
- Intermediate Metabolizers
- LCMS/MS
- Liquid Chromatography-Mass Spectrometry
- LOF
- Loss of Function
- LSMs
- Least-squares means
- PCI
- Percutaneous Coronary Intervention
- PD
- Pharmacodynamic
- PK
- Pharmacokinetic
- PM
- Poor Metabolizers
- TEAE
- Treatment Emergent Adverse Events
- USFDA
- United States Drug and Food Administration