Comparative sensitivity of laboratory animals used for preclinical convulsion risk assessment to drug-induced convulsion.

Abstract

Drug-induced convulsion is a serious concern in drug development, such that the convulsion liability of drug candidates must be evaluated in preclinical safety studies. However, information on the differences among species regarding their sensitivity to convulsions induced by convulsant drugs in humans remains limited. Here, we selected 11 test articles from several pharmacological classes and compared the sensitivities of three types of laboratory animal to convulsion. All 11 test articles were examined in mice via intraperitoneal injection and in rats via intravenous bolus; and 6 of the 11 test articles, selected mainly based on availabilities of data on drug plasma concentrations in humans at convulsion, were examined in non-human primates (NHPs) via intravenous infusion. Plasma concentrations of the test articles shortly after convulsion onset or 5 min after administration were measured. All 11 articles tested in mice, 10 of 11 articles tested in rats, and all 6 articles tested in NHPs induced convulsion with premonitory signs. Although there was a general tendency that rats and NHPs exhibited convulsions at lower plasma drug concentrations than did mice, the plasma concentrations at convulsion onset were generally comparable, within 3-fold differences, across the animal species. We conclude that the mice, rats, and NHPs examined in the present study generally showed similar sensitivities to convulsion induced by the test articles. Thus, each of these laboratory animals can be used for the assessment of convulsion risk in the early stages of drug development, depending on throughput, cost, and test article-specific requirements.