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.
摘要：
与5-羟色胺（5-HT）2B受体脱靶激活相关的心脏瓣膜病（心脏瓣膜疾病；CVD）已得到广泛认可，但在药物开发过程中仍然很难预测。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（Cmax），以计算安全裕度作为消除药物引起的心脏瓣膜病风险的检测阈值（>10）。在本文中,我们根据从有或无5-HT2B受体激活的药物获得的临床药效学和药代动力学数据,为临床前预测CVD风险提供了额外的建议.我们的研究表明，在体外基于5-HT2B细胞的功能测定中测试的分子的5-HT2B激动剂亲和力，放在透视他们的持续等离子体暴露（AUC），而不是他们的峰值等离子体暴露，Cmax(即，最大治疗暴露)为解释5-HT2B数据提供了坚实的基础，用于计算安全裕度，然后，准确区分与CVD的临床风险相关的药物与没有的药物（尽管具有一些激动剂5-HT2B活性）。此外,我们讨论了与5-HT2B受体激活相关的多器官纤维化的风险，经常被低估,然而，FAERS对5-HT2B激动剂的报道良好。我们认为，我们的建议有可能减轻CVD和纤维化临床发展的风险。
