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The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2015 May 15; Vol. 21 (10), pp. 2297-2304. Date of Electronic Publication: 2015 Mar 05. - Publication Year :
- 2015
-
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.<br />Experimental Design: We performed a phase I dose-escalation study according to the standard 3+3 design.<br />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.<br />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.<br /> (©2015 American Association for Cancer Research.)
- Subjects :
- Adult
Aged
Animals
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents toxicity
Dogs
Female
Humans
Inactivation, Metabolic
Kidney drug effects
Male
Maximum Tolerated Dose
Middle Aged
Pyrazoles pharmacokinetics
Pyrazoles toxicity
Pyridazines pharmacokinetics
Pyridazines toxicity
Rabbits
Rats
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Species Specificity
Antineoplastic Agents administration & dosage
Colorectal Neoplasms drug therapy
Kidney pathology
Pyrazoles administration & dosage
Pyridazines administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 21
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 25745036
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-14-3258