Abstract W P70: Pharmacokinetic Properties and Toxicity/safety Profiles of SP-8203, a Novel Neuroprotectant for Treatment of Cerebral Ischemic Stroke

Abstract

We recently identified a multi-target directed neuroprotectant SP-8203, which is now undergoing phase 1 clinical trial. Here we report the preclinical and clinical toxicity/safety profiles and pharmacokinetic properties of SP-8203. Single-dose and 28-day repeated-dose toxicity tests in Sprague Dawley rats, Beagle dogs, and Cynomolgus monkeys were performed by Chemon (Korea), MPI Research (USA), and Toxikon (USA) and Phase 1 clinical trial by ASAN medical center (korea). The genotoxicity was examined by the bacterial reverse mutation assay (AMES test), the chromosome aberration assay using Chinese hamster ovary and lung cells, and the micronucleus test in rat bone-marrow erythrocytes. The safety pharmacology studies evaluate acute neurobehavioral toxicities and pulmonary functions in male rats and cardiovascular toxicities in male Cynomolgus monkeys. Following a single-dose intravenous administration, the minimum lethal dose of SP-8203 was estimated to 60 mg/kg and the lethal dose 50 (LD50) was 83.3 mg/kg in rats. The No-Observable-Adverse-Effect-Level (NOAEL) of 4 week repeated dose of SP-8203 was 20 mg/kg/day in rats and 12 mg/kg/day in monkeys, when administered as an intravenous slow bolus injection for 5 min. However, when administered as an intravenous infusion for 30 min, the NOAEL in rats increased to 80 mg/kg/day or more. SP-8203 did not exert any genotoxicity. Safety pharmacology studies showed that NOAELs of neurobehavioral toxicity, pulmonary functions, and cardiovascular effects were 30 mg/kg, 30 mg/kg, and 10 mg/kg, respectively. In a single accelerating dose study in phase 1 clinical trial, no toxic responses were observed at doses up to 240mg in healthy subjects. Pharmacokinetics of SP-8203 evaluated after its intravenous administration in humans and rats showed that the AUCs and half-lives of SP-8203 were dose-dependently increased; thus the dose-normalized AUCs and half-lives were significantly elevated with increasing doses. However, the nonlinear PK properties are within safe ranges in humans and rats. Taken together, a series of toxicity/safety assessments showed that SP-8203 is quite safe and non-toxic at the doses for the treatment of cerebral ischemic stroke in humans.