主催: 日本毒性学会
会議名: 第47回日本毒性学会学術年会
開催日: 2020 -
[Background and purpose] Drug-induced convulsion is a serious adverse event in clinical trials; translation of convulsion risk from animals to humans is still a huge challenge because of species differences in susceptibility to drug-induced convulsions. In the present study, we chose a number of reference compounds to induce convulsions in mice, rats, and monkeys, to compare convulsion liability between humans and animals on the basis of plasma concentrations.
[Materials and methods] Mice (DBA/2) and rats (Crl: WI (Han)) were given different classes of reference compounds (a total of 11 compounds: e.g. Pilocarpine, 4-Aminopiridine, Pentylenetetrazole) intraperitoneally or intravenously. Plasma concentrations just after convulsion onset or completion of administration were measured by LC-MS/MS. Monkeys (cynomolgus) were dosed intravenously with a limited number of the reference compounds.
[Results and discussion] Convulsion was observed in mice, rats, and monkeys with the reference compounds, except for a GAT1 competitive inhibitor which did not induce convulsion in rats. There was a general trend for the unbound plasma levels in monkeys to be closest to those in humans at convulsion. Our results suggest that, when considering the amount of compound available at the drug discovery stage and time, combination approach of appropriate species is recommended for in vivo convulsion screenings to select the compound with low convulsion risk.