Unexpected renal toxicity associated with SGX523, a small molecule inhibitor of MET

Autor: Howard A. Burris, Ramesh K. Ramanathan, Michael Gordon, Lee S. Rosen, Isabelle Rooney, K. Zeh, Raymond W. Liu, Terence Rugg, Jeffrey R. Infante
Rok vydání: 2012
Předmět:
Zdroj: Investigational New Drugs. 31:363-369
ISSN: 1573-0646
0167-6997
DOI: 10.1007/s10637-012-9823-9
Popis: Purpose SGX523 is an orally bio-available, ATP competitive, small molecule inhibitor of MET, binding the kinase domain active site in a novel mode. Two phase 1, open-label, dose-escalation studies of SGX523 were conducted to evaluate both interrupted and continuous dosing schedules. Methods Thirty-six patients per study were planned to be enrolled. The first study explored a 21-day cycle with SGX523 administered on an intermittent schedule at a starting dose of 60 mg PO BID for 14 days followed by 7 days of rest. The second protocol explored a continuous 28-day dosing schedule with SGX523 administered at a starting dose of 20 mg PO BID for 28 days without rest. Results A total of 10 patients were enrolled, 2 on the intermittent dosing protocol and 8 on the continuous dosing protocol. All 6 patients that received daily doses of ≥ 80 mg developed unexpected renal failure manifested by an early rise of serum blood urea nitrogen and creatinine. Human PK analysis revealed the formation of two insoluble metabolites at levels not seen in the rat or dog preclinical toxicology studies. Subsequent primate toxicology and toxicokinetic evaluation replicated human findings, and histological examination of the monkey kidneys revealed the formation of crystals both within the renal tubules and within giant cell macrophages. Conclusion Two-species toxicology studies of SGX523 did not predict the occurrence of renal toxicity in the human. Subsequent primate toxicology studies suggest the cause of the renal failure seen in humans was a crystal nephropathy secondary to insoluble metabolites. SGX523 is no longer in clinical development.
Databáze: OpenAIRE
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