Preclinical safety, toxicokinetics and metabolism of BIIB131, a novel prothrombolytic agent for acute stroke

BIIB131, a small molecule, is currently in Phase 2 for the treatment of acute ischemic stroke. Safety and metabolism of BIIB131 were evaluated following intravenous administration to rats and monkeys. Exposure increased dose-proportionally in rats up to 60 mg/kg and more than dose-proportionally in monkeys at greater than 10 mg/kg accompanied by prolonged half-life and safety findings. The BIIB131 was poorly metabolized in microsomes with no inhibition of CYPs. BIIB131-glucuronide, formed by UGT1A1, accounted for 21.5% metabolism in human hepatocytes and 28–40% in rat bile. In rats, excretion was primarily via the bile. BIIB131 inhibited the hERG and Nav1.5 cardiac channels by 39% but showed no effect on cardiovascular parameters in monkeys. Toxicology findings were limited to reversable hematuria, changes in urinary parameters and local effects. A MTD of 30 mg/kg was established in monkeys, the most sensitive species, at total plasma Cmax and AUC of 6- and 14-fold greater than the NOAEL. The Phase 1 study started with intravenous 0.05 mg/kg and ascended to 6.0 mg/kg which corresponded to safety margins of 147- to 0.9-fold (based on Cmax) within the linear drug exposure. Thus, the preclinical profile of BIIB131 has been appropriately characterized and supports its further clinical development. •Drug is metabolized by UGT1A1 with no effect of CYPs on metabolism.•Saturation of glucuronidation and/or hepatobiliary excretion in monkey results in greater exposure to parent drug and toxicity.•Maximum tolerable dose is 6-fold greater than the safe dose.•Inhibition of cardiac channels in vitro but no effect on CV parameters monkeys.•Rats showed greater glucuronidation and/or hepatobiliary excretion when compared to monkeys.•Possibility of drug-drug interaction with UGT1A1 substrates or inhibitors.•Possibility of higher exposure to parent drug that may require a dose reduction in UGT1A1-poor metabolizers.