Phase 1 study of novel anti-platelet agent to overcome pharmacogenomic limitations of clopidogrel.

IF 2.8 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

Open Heart Pub Date : 2025-02-11 DOI:10.1136/openhrt-2024-003088

Anil Pareek, Nitin Chandurkar, Vivek Raut, Kumar Naidu

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引用次数: 0

Abstract

Aims: Clopidogrel is the most commonly prescribed thienopyridine as part of dual anti-platelet 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 compared with standard dosage regimen of clopidogrel based on their CYP2C19 genotyping.

Methods: Two CYP2C19 genotype-based groups were identified, that is, poor metabolisers and extensive metabolisers, with 20 subjects in each group (n=40) for participating in a randomised, two-period, crossover study. Each study period lasted 6 days including administration of loading and maintenance doses of AT-10 (40 mg/10 mg) or clopidogrel (300 mg/75 mg). 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 6 hours postdose (loading dose) (AT-10: clopidogrel; 73.30% vs 18.53%) and 6 hours postdose 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 metaboliser group was significantly higher than the clopidogrel treatments in extensive metaboliser group.Overall pharmacokinetic comparison in all subjects indicates that AT-10 gives greater exposure to active Metabolite H4 than clopidogrel.

Conclusion: AT-10 showed better inhibition of platelet aggregation in poor metabolizers as compared to Clopidogrel. AT-10 may emerge as a potential alternative to Clopidogrel as an anti-platelet drug. It can be further developed in clinical studies for the unmet medical needs in management of CVDs and overcome the pharmacogenomic limitations of Clopidogrel.

Trial registration number: Clinical Trial Registry-India URL: http://ctri.nic.in.

Registration number: CTRI/2021/03/032206.

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新型抗血小板药物克服氯吡格雷药物基因组学局限性的一期研究。

目的：氯吡格雷是最常用的噻诺吡啶作为双重抗血小板治疗心血管疾病的一部分。然而，氯吡格雷反应性表现出基于CYP2C19多态性的变异性。因此，我们计划了一项研究，目的是根据印度健康受试者的CYP2C19基因分型，与氯吡格雷标准给药方案比较，评估新型噻吩吡啶类抗血小板药物AT-10在健康受试者中的安全性、耐受性、药效学和药代动力学。方法：确定基于CYP2C19基因型的两组，即代谢不良者和代谢广泛者，每组20例（n=40），进行随机、两期交叉研究。每个研究周期为6天，包括给药负荷和维持剂量AT-10 （40 mg/10 mg）或氯吡格雷（300 mg/75 mg）。在第1天和第6天以不同的时间间隔评估药代动力学和药效学。结果：药理学参数的总体结果显示，at -10和氯吡格雷在给药后6小时（负荷剂量）对所有受试者血小板聚集的平均抑制率为% (at -10：氯吡格雷；73.30% vs 18.53%)和第6天给药后6小时（维持剂量）(AT-10：氯吡格雷；83.41% vs 51.19%)，显著高于氯吡格雷组。此外，低代谢组AT-10治疗对血小板聚集的抑制作用显著高于高代谢组氯吡格雷治疗。所有受试者的总体药代动力学比较表明，AT-10比氯吡格雷更容易暴露于活性代谢物H4。结论：与氯吡格雷相比，AT-10对代谢不良者的血小板聚集具有更好的抑制作用。AT-10可能成为氯吡格雷抗血小板药物的潜在替代品。它可以在临床研究中进一步发展，以满足心血管疾病管理中未满足的医疗需求，并克服氯吡格雷的药物基因组学局限性。临床试验注册编号：印度临床试验注册网址：http://ctri.nic.in.Registration编号：CTRI/2021/03/032206。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Open Heart CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

4.60

自引率

3.70%

发文量

145

审稿时长

20 weeks

期刊介绍： Open Heart is an online-only, open access cardiology journal that aims to be “open” in many ways: open access (free access for all readers), open peer review (unblinded peer review) and open data (data sharing is encouraged). The goal is to ensure maximum transparency and maximum impact on research progress and patient care. The journal is dedicated to publishing high quality, peer reviewed medical research in all disciplines and therapeutic areas of cardiovascular medicine. Research is published across all study phases and designs, from study protocols to phase I trials to meta-analyses, including small or specialist studies. Opinionated discussions on controversial topics are welcomed. Open Heart aims to operate a fast submission and review process with continuous publication online, to ensure timely, up-to-date research is available worldwide. The journal adheres to a rigorous and transparent peer review process, and all articles go through a statistical assessment to ensure robustness of the analyses. Open Heart is an official journal of the British Cardiovascular Society.