ABSTRACT
1. Idasanutlin (RG7388) is a potent p53-MDM2 antagonist currently in clinical development for treatment of cancer. The purpose of the present studies was to investigate the cause of marked decrease in plasma exposure after repeated oral administration of RG7388 in monkeys and whether the autoinduction observed in monkeys is relevant to humans. 2. In monkey liver and intestinal microsomes collected after repeated oral administration of RG7388 to monkeys, significantly increased activities of homologue CYP3A8 were observed (ex vivo). Investigation using a physiologically based pharmacokinetic (PBPK) model suggested that the loss of exposure was primarily due to induction of metabolism in the gut of monkeys. 3. Studies in monkey and human primary hepatocytes showed that CYP3A induction by RG7388 only occurred in monkey hepatocytes but not in human hepatocytes, which suggests the observed CYP3A induction is monkey specific. 4. The human PK data obtained from the first cohorts confirmed the lack of relevant induction as predicted by the human hepatocytes and the PBPK modelling based on no induction in humans.
Subject(s)
Antineoplastic Agents/pharmacology , Macaca fascicularis/physiology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Pyrrolidines/pharmacology , para-Aminobenzoates/pharmacology , Animals , Antineoplastic Agents/metabolism , Humans , Proto-Oncogene Proteins c-mdm2/metabolism , Pyrrolidines/metabolism , para-Aminobenzoates/metabolismABSTRACT
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