The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation.
Clin Cancer Res
; 21(10): 2297-2304, 2015 May 15.
Article
em En
| MEDLINE
| ID: mdl-25745036
ABSTRACT
PURPOSE:
The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor. EXPERIMENTALDESIGN:
We performed a phase I dose-escalation study according to the standard 3+3 design.RESULTS:
Even at subtherapeutic doses, mild though recurrent renal toxicity was observed in virtually all patients. Renal toxicity had not been observed in preclinical studies in rats and dogs. Additional preclinical studies pointed toward the rabbit as a suitable toxicology model, as the formation of the M10 metabolite of JNJ-38877605 specifically occurred in rabbits and humans. Additional toxicology studies in rabbits clearly demonstrated that JNJ-38877605 induced species-specific renal toxicity. Histopathological evaluation in rabbits revealed renal crystal formation with degenerative and inflammatory changes. Identification of the components of these renal crystals revealed M1/3 and M5/6 metabolites. Accordingly, it was found that humans and rabbits showed significantly increased systemic exposure to these metabolites relative to other species. These main culprit insoluble metabolites were generated by aldehyde oxidase activity. Alternative dosing schedules of JNJ-3877605 and concomitant probenecid administration in rabbits failed to prevent renal toxicity at dose levels that could be pharmacologically active.CONCLUSIONS:
Combined clinical and correlative preclinical studies suggest that renal toxicity of JNJ-38877605 is caused by the formation of species-specific insoluble metabolites. These observations preclude further clinical development of JNJ-38877605.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Piridazinas
/
Neoplasias Colorretais
/
Rim
/
Antineoplásicos
Tipo de estudo:
Clinical_trials
/
Etiology_studies
Limite:
Adult
/
Aged
/
Animals
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Clin Cancer Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Reino Unido