Regulatory Forum Review*: Utility of in Vitro Secondary Pharmacology Data to Assess Risk of Drug-induced Valvular...

Drug-induced valvular heart disease (VHD) is a serious side effect linked to long-term treatment with 5-hydroxytryptamine (serotonin) receptor 2B (5-HT_2B) agonists. Safety assessment for off-target pharmacodynamic activity is a common approach used to screen drugs for this undesired property. Such studies include in vitro assays to determine whether the drug is a 5-HT_2B agonist, a necessary pharmacological property for development of VHD. Measures of in vitro binding affinity (IC₅₀, K_i) or cellular functional activity (EC₅₀) are often compared to maximum therapeutic free plasma drug levels ( fC_max) from which safety margins (SMs) can be derived. However, there is no clear consensus on what constitutes an appropriate SM under various therapeutic conditions of use. The strengths and limitations of SM determinations and current risk assessment methodology are reviewed and evaluated. It is concluded that the use of SMs based on K_i values, or those relative to serotonin (5-HT), appears to be a better predictor than the use of EC₅₀ or EC₅₀/human fC_max values for determining whether known 5-HT_2B agonists have resulted in VHD. It is hoped that such a discussion will improve efforts to reduce this preventable serious drug-induced toxicity from occurring and lead to more informed risk assessment strategies.