Concordance of the toxicity of pharmaceuticals in humans and in animals

This report summarizes the results of a multinational pharmaceutical compan y survey and the outcome of an International Life Sciences Institute (ILSI) Workshop (April 1999), which served to better understand concordance of th e toxicity of pharmaceuticals observed in humans with that observed in expe rimental animals. The Workshop included representatives from academia, the multinational pharmaceutical industry, and international regulatory scienti sts. The main aim of this project was to examine the strengths and weakness es of animal studies to predict human toxicity (RT). The database was devel oped from a survey which covered only those compounds where HTs were identi fied during clinical development of new pharmaceuticals, determining whethe r animal toxicity studies identified concordant target organ toxicities in humans. Data collected included codified compounds, therapeutic category, t he HT organ system affected, and the species and duration of studies in whi ch the corresponding HT was either first identified or not observed. This s urvey includes input from 12 pharmaceutical companies with data compiled fr om 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 fo r 63% of HTs and rodents alone for 43%. The highest incidence of overall co ncordance was seen in hematological, gastrointestinal, and cardiovascular H Ts, and the least was seen in cutaneous HT. Where animal models, in one or more species, identified concordant RT, 94% were first observed in studies of 1 month or less in duration. These survey results support the value of i n vivo toxicology studies to predict for many significant HTs associated wi th pharmaceuticals and have helped to identify HT categories that may benef it from improved methods. (C) 2000 Academic Press.