title: 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.
authors.affiliation: a Pharmaceutical Sciences, Roche Innovation Center , New York , NY , USA .|b Novartis Oncology Business Unit , East Hanover , NJ , USA .
authors.forename: Kelli J
authors.initials: KJ
authors.lastname: Glenn
authors.affiliation: a Pharmaceutical Sciences, Roche Innovation Center , New York , NY , USA .
authors.forename: Li J
authors.initials: LJ
authors.lastname: Yu
authors.affiliation: a Pharmaceutical Sciences, Roche Innovation Center , New York , NY , USA .|c Department of Clinical Pharmacology , Array BioPharma Inc , Boulder , CO , USA .
authors.forename: Micaela B
authors.initials: MB
authors.lastname: Reddy
authors.affiliation: a Pharmaceutical Sciences, Roche Innovation Center , New York , NY , USA .|d AstraZeneca , Waltham , MA , USA .
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Fretland
authors.affiliation: h Roche Innovation Center , Basel , Switzerland.
authors.forename: Neil
authors.initials: N
authors.lastname: Parrott
authors.affiliation: a Pharmaceutical Sciences, Roche Innovation Center , New York , NY , USA .|e Vertex Pharmaceuticals , Boston , MA , USA .
authors.forename: Sazzad
authors.initials: S
authors.lastname: Hussain
authors.affiliation: a Pharmaceutical Sciences, Roche Innovation Center , New York , NY , USA .|f Genentech Inc , South San Francisco , CA , USA .
authors.forename: Mary
authors.initials: M
authors.lastname: Palacios
authors.affiliation: a Pharmaceutical Sciences, Roche Innovation Center , New York , NY , USA .
authors.forename: Faye
authors.initials: F
authors.lastname: Vazvaei
authors.affiliation: g Clinical Pharmacology, Roche Innovation Center , New York , NY , USA , and.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhi
authors.affiliation: h Roche Innovation Center , Basel , Switzerland.
authors.forename: Dietrich
authors.initials: D
authors.lastname: Tuerck
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology*; D062366:para-Aminobenzoates / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011759:Pyrrolidines; C586849:RG7388; D062366:para-Aminobenzoates; D051736:Proto-Oncogene Proteins c-mdm2
keywords: CYP3A; MDM2 antagonist; PBPK modelling; RG7388; idasanutlin; monkey-specific autoinduction; pharmacokinetics