药物诱导磷脂沉积症的安全性问题和风险控制策略

Safety concerns of drug-induced phospholipidosis and strategy for risk management

药物诱导磷脂沉积症(PLD)是指药物和磷脂在细胞溶酶体中过度沉积的现象。不同结构的阳离子两亲性药物可通过不同的作用机制诱导PLD。部分小分子化合物在诱导PLD的同时,还导致靶组织器官毒性和功能损伤。在审评实践中,当缺少足够证据排除PLD相关临床安全性风险时,监管机构倾向于认为药物诱导PLD是给药相关的不良反应。随着对PLD安全性风险的深入理解,制定科学筛选和临床风险防控措施可以更好地指导新药研发中的候选化合物选择,并增加监管机构批准候选化合物进入临床试验的信心。本文综述了PLD的机制、相关非临床安全性风险以及分级风险防控策略,对审评案例进行了讨论,供业内参考。

Drug-induced phospholipdosis（ PLD） is an excessive accumulation of phospholipids and drugs in lysosomes,which is likely to occur by separate mechanisms when triggered by cationic amphiphilic drugs of different structures. A small number of chemicals are able to cause concurrent organ toxicity and functional damage while inducing PLD. For this reason,when lack of evidence to preclude the clinical safety risks,some regulatory authorities tend to consider PLD to be adverse. To enact a strategy of science-based selection and risk prevention in clinical trials will direct the lead compound screen in early drug development and strengthen confidence of the regulatory authorizes when approving a candidate into clinical trials along with the deeper understanding of the risks associated with PLD. We here reviewed the mechanisms and safety concerns of PLD,and tried to summarize a tiered risk management policy of drug-induced PLD. A discussion of case study was provided as a reference for the industry.