Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A
Pfizer Inc., Groton, Connecticut, USA.
Regul Toxicol Pharmacol. 2000 Aug;32(1):56-67. doi: 10.1006/rtph.2000.1399.
This report summarizes the results of a multinational pharmaceutical company survey and the outcome of an International Life Sciences Institute (ILSI) Workshop (April 1999), which served to better understand concordance of the toxicity of pharmaceuticals observed in humans with that observed in experimental animals. The Workshop included representatives from academia, the multinational pharmaceutical industry, and international regulatory scientists. The main aim of this project was to examine the strengths and weaknesses of animal studies to predict human toxicity (HT). The database was developed from a survey which covered only those compounds where HTs were identified during clinical development of new pharmaceuticals, determining whether animal toxicity studies identified concordant target organ toxicities in humans. Data collected included codified compounds, therapeutic category, the HT organ system affected, and the species and duration of studies in which the corresponding HT was either first identified or not observed. This survey includes input from 12 pharmaceutical companies with data compiled from 150 compounds with 221 HT events reported. Multiple HTs were reported in 47 cases. The results showed the true positive HT concordance rate of 71% for rodent and nonrodent species, with nonrodents alone being predictive for 63% of HTs and rodents alone for 43%. The highest incidence of overall concordance was seen in hematological, gastrointestinal, and cardiovascular HTs, and the least was seen in cutaneous HT. Where animal models, in one or more species, identified concordant HT, 94% were first observed in studies of 1 month or less in duration. These survey results support the value of in vivo toxicology studies to predict for many significant HTs associated with pharmaceuticals and have helped to identify HT categories that may benefit from improved methods.
本报告总结了一家跨国制药公司的调查结果以及国际生命科学研究所（ILSI）研讨会（1999年4月）的成果，该研讨会旨在更好地了解人类中观察到的药物毒性与实验动物中观察到的药物毒性的一致性。研讨会包括来自学术界、跨国制药行业和国际监管科学家的代表。该项目的主要目的是检验动物研究在预测人类毒性（HT）方面的优势和劣势。数据库是根据一项调查建立的，该调查仅涵盖那些在新药物临床开发过程中确定了HT的化合物，以确定动物毒性研究是否识别出人类中一致的靶器官毒性。收集的数据包括编码化合物、治疗类别、受影响的HT器官系统，以及首次识别或未观察到相应HT的研究物种和持续时间。这项调查包括来自12家制药公司的输入数据，这些数据是从150种化合物中汇编而来的，报告了221起HT事件。47例报告了多种HT。结果显示，啮齿动物和非啮齿动物物种的真实阳性HT一致性率为71%，仅非啮齿动物可预测63%的HT，仅啮齿动物可预测43%的HT。总体一致性发生率最高的是血液学、胃肠道和心血管HT，最低的是皮肤HT。在一个或多个物种的动物模型中识别出一致的HT的情况下，94%是在持续时间为1个月或更短的研究中首次观察到的。这些调查结果支持了体内毒理学研究在预测与药物相关的许多重要HT方面的价值，并有助于识别可能受益于改进方法的HT类别。
