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 C _max and AUC of 6- and 14-fold, respectively, 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 (for C _max ) within the linear drug exposure. Thus, the preclinical profile of BIIB131 has been appropriately characterized and supports its further clinical development.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Keiko Hasegawa reports financial support was provided by Japan Science and Technology Agency. Keiji Hasumi reports financial support was provided by Japan Science and Technology Agency. Naoko Nishimura reports financial support was provided by Japan Science and Technology Agency. Vic Kostrubsky reports a relationship with Biogen Inc that includes: employment and equity or stocks. Chungang Gu reports a relationship with Biogen Inc that includes: employment and equity or stocks. Cathy Muste reports a relationship with Biogen Inc that includes: employment and equity or stocks. Melissa Kirkland reports a relationship with Biogen that includes: employment and equity or stocks. Ying Liu reports a relationship with Biogen Inc that includes: employment and equity or stocks. Long Yuan reports a relationship with Biogen Inc that includes: employment and equity or stocks. Keiko Hasegawa reports a relationship with TMS Co Ltd that includes: employment and equity or stocks. Keiji Hasumi reports a relationship with TMS Co Ltd that includes: employment and equity or stocks. Naoko Nishimura reports a relationship with TMS Co Ltd that includes: consulting or advisory, employment, and equity or stocks.
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