Preclinical mitigation of 5-HT2B agonism-related cardiac valvulopathy revisited

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
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Abstract

Cardiac valvulopathy (Cardiac Valve Disease; CVD) associated with off-target activation of the 5-hydroxytryptamine (5-HT) 2B receptor has been well recognized, but is still poorly predicted during drug development. The regulatory guidance proposes the use of 5-HT2B binding data (i.e., Ki values) and free maximum therapeutic exposure (Cmax) to calculate safety margins as a threshold of detection (>10) for eliminating the risk of drug-induced cardiac valvulopathy. In this paper, we provide additional recommendations for preclinical prediction of CVD risk based on clinical pharmacodynamic and pharmacokinetic data obtained from drugs with or without 5-HT2B receptor activation. Our investigations showed that 5-HT2B agonist affinity of molecules tested in an in vitro 5-HT2B cell-based functional assay, placed in perspective to their sustained plasma exposure (AUCs) and not to their peak plasma exposure, Cmax (i.e., maximum therapeutic exposure) provide a solid basis for interpreting 5-HT2B data, for calculating safety margins and then, accurately differentiate drugs associated with a clinical risk of CVD from those which are not (despite having some agonist 5-HT2B activity). In addition, we discuss the risk of multi-organ fibrosis linked to 5-HT2B receptor activation, often underestimated, however well reported in FAERS for 5-HT2B agonists. We believe that our recommendations have the potential to mitigate the risk for the clinical development of CVD and fibrosis.

再论 5-HT2B 激动剂相关心脏瓣膜病的临床前缓解措施
与 5- 羟色胺 (5-HT) 2B 受体的脱靶激活有关的心脏瓣膜病(CVD)已得到广泛认可,但在药物开发过程中对其预测仍然不足。监管指南建议使用 5-HT2B 结合数据(即 Ki 值)和自由最大治疗暴露量(Cmax)来计算安全系数,作为消除药物诱发心脏瓣膜病风险的检测阈值 (>10)。在本文中,我们根据从有或没有 5-HT2B 受体激活的药物中获得的临床药效学和药代动力学数据,为临床前预测心血管疾病风险提供了更多建议。我们的研究表明,在体外 5-HT2B 细胞功能检测中测试的分子的 5-HT2B 激动剂亲和力,与其持续血浆暴露量(AUCs)而非其峰值血浆暴露量、Cmax(即最大治疗暴露量)有关,为解释 5-HT2B 数据、计算安全系数以及准确区分与心血管疾病临床风险有关的药物和与心血管疾病临床风险无关的药物(尽管具有一定的 5-HT2B 激动剂活性)提供了坚实的基础。此外,我们还讨论了与 5-HT2B 受体激活相关的多器官纤维化风险,这种风险往往被低估,但在 FAERS 中却有关于 5-HT2B 激动剂的详细报告。我们相信,我们的建议有可能降低心血管疾病和纤维化的临床发展风险。
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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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