Investigating the effect of autoinduction in cynomolgus monkeys of a novel anticancer MDM2 antagonist, idasanutlin, and relevance to humans

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.

• CYP3A
• idasanutlin
• MDM2 antagonist
• monkey-specific autoinduction
• PBPK modelling
• pharmacokinetics
• RG7388

Acknowledgements

We thank Lynn Grey and Michelle Chang for study assistance, Michael Pignatello for evaluation of toxicology studies as the lead toxicologist for the programme, and Scott Williams of Covance Laboratories, Inc., who supported all toxicology studies as the study director, which were funded by F. Hoffmann-La Roche. We greatly appreciate the critical review of the manuscript and valuable comments provided by Drs Gwen Nichols and Gerald Miwa.

Declaration of interest

This work was supported by F. Hoffmann-La Roche Ltd. All authors were employed by Roche at the time this study was performed. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche.