Chatman Linda A, Morton Daniel, Johnson Theodore O, Anway Susan D
Pathology Department, Drug Safety Research and Development, Pfizer, Inc., Groton, CT, USA.
Toxicol Pathol. 2009 Dec;37(7):997-1005. doi: 10.1177/0192623309352496.
Drug-induced phospholipidosis (PL) is an excessive accumulation of phospholipids and drug in lysosomes. Phospholipidosis signals a change in cell membrane integrity and accumulation of intracellular drug or metabolite in tissues. The sensitivity and susceptibility of preclinical models to detect PL vary with therapeutic agents, and PL is expected to be reversible after discontinuation of drug treatment. The prevailing scientific opinion is that PL by itself is not adverse; however, some regulatory authorities consider PL to be adverse because a small number of chemicals are able to cause PL and concurrent organ toxicity. Until a greater understanding of PL emerges, a well-thought-out risk management strategy for PL will increase confidence in safety and improve selection and development of new drugs. This paper provides a tiered approach to risk management of drug-induced PL. It begins with use of in silico and in vitro tools to design and select compounds with reduced potential to produce PL. Early in vivo studies in two species are used to better characterize potential for toxicity and PL. Finally, routine risk management tools (i.e., translational biomarkers, assessment of reversibility) are used to support confidence in safety of compounds that induce PL in animals.
药物性磷脂沉积症（PL）是磷脂和药物在溶酶体中的过度蓄积。磷脂沉积症表明细胞膜完整性发生改变，以及细胞内药物或代谢产物在组织中的蓄积。临床前模型检测PL的敏感性和易感性因治疗药物而异，并且预计在停药后PL是可逆的。目前普遍的科学观点是，PL本身并无不良影响；然而，一些监管机构认为PL是不良的，因为少数化学物质能够导致PL并同时引发器官毒性。在对PL有更深入的了解之前，精心制定的PL风险管理策略将增强对安全性的信心，并改善新药的选择和研发。本文提供了一种药物性PL风险管理的分层方法。首先使用计算机模拟和体外工具来设计和选择产生PL可能性降低的化合物。在两个物种中进行早期体内研究，以更好地表征毒性和PL的可能性。最后，使用常规风险管理工具（即转化生物标志物、可逆性评估）来支持对在动物中诱导PL的化合物安全性的信心。
