Dahal Upendra P, Rock Brooke M, Rodgers John, Shen Xiaomeng, Wang Zhe, Wahlstrom Jan L
Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California.
Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California
Drug Metab Dispos. 2022 May;50(5):600-612. doi: 10.1124/dmd.121.000798. Epub 2022 Feb 13.
Sotorasib is a first-in-class, targeted covalent inhibitor of Kirsten rat sarcoma viral oncogene homolog (KRAS) approved by the FDA to treat patients with locally advanced or metastatic non-small cell lung cancer with the KRAS mutation. The mass balance, excretion, and metabolism of [C]-sotorasib was characterized in rats and dogs after a single dose of 60 or 500 mg/kg, respectively. Mean recovery was >90% for both species. Excretion of unchanged sotorasib was a minor pathway in rats, accounting for <4% of administered dose in urine and <7% of administered dose in feces. Approximately 66% of administered dose was recovered in the bile from bile duct cannulated rats as metabolites. Excretion of unchanged sotorasib was the major excretion pathway in dogs, likely caused by solubility-limited absorption. Major pathways of sotorasib biotransformation included glutathione conjugation and oxidative metabolism. In vitro experiments demonstrated that nonenzymatic conjugation (Michael addition) was the primary mechanism of the reaction with glutathione. Extended radioactivity profiles in blood and plasma were observed in rats, but not dogs, after dosing with [C]-sotorasib. In vitro experiments demonstrated that sotorasib-protein adducts were observed with both rat hemoglobin and serum albumin, explaining the extended radioactivity profile. SIGNIFICANCE STATEMENT: This study characterized the mass balance, excretion, and metabolism of [C]-sotorasib, a covalent Kirsten rat sarcoma viral oncogene homolog G12C inhibitor, in rats and dogs. Rapid absorption and extensive metabolism of sotorasib was observed in rats, while sotorasib was primarily excreted unchanged in dog feces, likely due to solubility-limited absorption. Protein adducts with rat hemoglobin and serum albumin were characterized, explaining observed extended blood and plasma radioactivity profiles. The primary biotransformation pathway, glutathione conjugation, was mediated through nonenzymatic conjugation.
索托拉西布是一种一流的、靶向共价抑制剂，可抑制 Kirsten 大鼠肉瘤病毒癌基因同源物（KRAS），已获美国食品药品监督管理局（FDA）批准，用于治疗患有 KRAS 突变的局部晚期或转移性非小细胞肺癌患者。分别给予大鼠和犬 60 或 500 mg/kg 的单剂量[C] - 索托拉西布后，对其质量平衡、排泄和代谢进行了表征。两种物种的平均回收率均>90%。在大鼠中，未改变的索托拉西布排泄是一条次要途径，在尿液中占给药剂量的<4%，在粪便中占给药剂量的<7%。在胆管插管的大鼠胆汁中，约 66%的给药剂量以代谢物形式回收。未改变的索托拉西布排泄是犬的主要排泄途径，可能是由于溶解度限制吸收所致。索托拉西布生物转化的主要途径包括谷胱甘肽结合和氧化代谢。体外实验表明，非酶结合（迈克尔加成）是与谷胱甘肽反应的主要机制。用[C] - 索托拉西布给药后，在大鼠而非犬中观察到血液和血浆中的放射性分布延长。体外实验表明，在大鼠血红蛋白和血清白蛋白中均观察到索托拉西布 - 蛋白质加合物，这解释了放射性分布延长的现象。意义声明：本研究表征了共价 Kirsten 大鼠肉瘤病毒癌基因同源物 G12C 抑制剂[C] - 索托拉西布在大鼠和犬中的质量平衡、排泄和代谢。在大鼠中观察到索托拉西布快速吸收和广泛代谢，而索托拉西布主要以未改变的形式排泄到犬粪便中，可能是由于溶解度限制吸收。对与大鼠血红蛋白和血清白蛋白的蛋白质加合物进行了表征，解释了观察到的血液和血浆放射性分布延长的现象。主要生物转化途径谷胱甘肽结合是通过非酶结合介导的。
