Dumotier, Berengere and Urban, Laszlo (2024) Preclinical mitigation of 5-HT2B agonism-related cardiac valvulopathy revisited. Journal of pharmacological and toxicological methods, 128 (107542).

Abstract

Cardiac valvulopathy (Cardiac Valve Disease; CVD) associated with off-target activation of the 5-hydroxytryptamine (5-HT) 2B receptor has been well recognized, however still today, poorly predicted during drug development. The regulatory guidance proposes the use of 5-HT2B binding data (i.e., Kis values) and of the free maximal 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 (i.e., Area Under the Curve) and not to their peak plasma exposure, Cmax (i.e., maximum therapeutic exposure) provide a solid basement for interpreting 5-HT2B data, for calculating safety margins and then, accurately differentiating drugs associated to a clinical risk of CVD from those which are not (despite for some agonist 5-HT2B activities). 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 optimize the prevention the clinical development of CVD and fibrosis.

Item Type:	Article
Keywords:	5-HT2B, serotonin, human, receptor, heart valve disease, drug evaluation, preclinical, drug safety
Date Deposited:	17 Sep 2024 00:45
Last Modified:	17 Sep 2024 00:45
URI:	https://oak.novartis.com/id/eprint/53943