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

Vick Kostrubsky; Ying Liu; Cathy Muste; Chungang Gu; Melissa Kirkland; Naoko Nishimura; Keiko Hasegawa; Keiji Hasumi; Long Yuan

doi:10.1016/j.yrtph.2023.105498

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

Regul Toxicol Pharmacol. 2023 Dec:145:105498. doi: 10.1016/j.yrtph.2023.105498. Epub 2023 Sep 29.

Authors

Vick Kostrubsky¹, Ying Liu², Cathy Muste², Chungang Gu², Melissa Kirkland³, Naoko Nishimura⁴, Keiko Hasegawa⁴, Keiji Hasumi⁵, Long Yuan²

Affiliations

¹ Nonclinical Safety Science, Biogen, Inc., 225 Binney Street, Cambridge, MA, 02142, USA. Electronic address: zlat77@sbcglobal.net.
² Drug Metabolism and Pharmacokinetics, Biogen, Inc., 225 Binney Street, Cambridge, MA, 02142, USA.
³ Nonclinical Safety Science, Biogen, Inc., 225 Binney Street, Cambridge, MA, 02142, USA.
⁴ Division of Research and Development, TMS Co., Ltd., Tokyo, Japan.
⁵ Division of Research and Development, TMS Co., Ltd., Tokyo, Japan; Department of Applied Biological Science, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan.

PMID: 37778433
DOI: 10.1016/j.yrtph.2023.105498

Abstract

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.

Keywords: Biliary excretion; Bilirubin; Cardiac channels; Glucuronidation; Metabolism; Monkeys; Rats; Safety margins; Saturation; Stroke treatment; Thrombolytic; UGT1A1; hERG; hNav1.5.

MeSH terms

Animals
Bile / metabolism
Humans
Injections, Intravenous
Ischemic Stroke* / metabolism
Rats
Rats, Sprague-Dawley
Toxicokinetics