Mercapturate pathway metabolites of sotorasib, a covalent inhibitor of KRAS G12C , are associated with renal toxicity in the Sprague Dawley rat.

Autor: Werner JA; Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA. Electronic address: jowerner@amgen.com., Davies R; Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA., Wahlstrom J; Amgen Research, Pharmacokinetics and Drug Metabolism, South San Francisco, CA, USA., Dahal UP; Amgen Research, Pharmacokinetics and Drug Metabolism, South San Francisco, CA, USA., Jiang M; Amgen Research, Pharmacokinetics and Drug Metabolism, South San Francisco, CA, USA., Stauber J; Imabiotech Corp, Billerica, MA, USA., David B; Imabiotech Corp, Billerica, MA, USA., Siska W; Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA., Thomas B; Amgen Research Operations, Thousand Oaks, CA, USA., Ishida K; Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA., Humphreys WG; Aranmore Pharma Consulting, Lawrenceville, NJ, USA., Lipford JR; Amgen Research, Oncology, Thousand Oaks, CA, USA., Monticello TM; Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2021 Jul 15; Vol. 423, pp. 115578. Date of Electronic Publication: 2021 May 15.
DOI: 10.1016/j.taap.2021.115578
Abstrakt: Sotorasib is a first-in class KRAS G12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. In the nonclinical toxicology studies of sotorasib, the kidney was identified as a target organ of toxicity in the rat but not the dog. Renal toxicity was characterized by degeneration and necrosis of the proximal tubular epithelium localized to the outer stripe of the outer medulla (OSOM), which suggested that renal metabolism was involved. Here, we describe an in vivo mechanistic rat study designed to investigate the time course of the renal toxicity and sotorasib metabolites. Renal toxicity was dose- and time-dependent, restricted to the OSOM, and the morphologic features progressed from vacuolation and necrosis to regeneration of tubular epithelium. The renal toxicity correlated with increases in renal biomarkers of tubular injury. Using mass spectrometry and matrix-assisted laser desorption/ionization, a strong temporal and spatial association between renal toxicity and mercapturate pathway metabolites was observed. The rat is reported to be particularly susceptible to the formation of nephrotoxic metabolites via this pathway. Taken together, the data presented here and the literature support the hypothesis that sotorasib-related renal toxicity is mediated by a toxic metabolite derived from the mercapturate and β-lyase pathway. Our understanding of the etiology of the rat specific renal toxicity informs the translational risk assessment for patients.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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