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Mar 22, 2015
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In Silico Modeling Can Predict the Unforeseen Renal Failure Caused by SGX523, a c-MET Kinase Inhibitor

Introduction

  • SGX523 is a quinoline containing,c-MET kinase inhibitor with an IC50 of 4nM (BuchananSGetal.,2009)
    • Inhibited the growth of human glioblastoma lung and gastric cancer xenografts in mice
  • In a Phase 1 clinical trial, all six patients that received an 80 mg dose developed renal failure (InfanteJRetal.,2013)
  • Follow-up studies revealed that the cause of renal toxicity was drug-induced nephropathy due to a metabolite of SGX523 that was not detected in preclinical studies (DiamondSetal.,2010)
    • Aldehydeoxidase (AOX) transforms the quinoline ring into a quinolinone
    • Generation of the quinolinone metabolite(M11)is species-dependent
      • Formed in human and monkey liverS-9 but not in dogS-9incubations
  • We used predicted properties as inputs to PBPK simulations in order to predict the toxicokinetics of SGX523 and M11.

SOT 54th Annual Meeting and ToxExpo, March 22-26, 2015, San Diego, CA

By Michael Lawless, John DiBella, and Michael B. Bolger

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