title: Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation.
abstract: 1. AMG 232 is a novel inhibitor of the p53-MDM2 protein-protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data. 2. AMG 232 exhibited low clearance (<0.25 × Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74 × Qh) and low oral exposure in dogs (18%). 3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered (14)C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species. 4. The in vitro-in vivo correlation of AMG 232 clearance was within 2-fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials.
authors: Department of Pharmacokinetics and Drug Metabolism and.
authors: Qiuping
authors: Q
authors: Ye
authors: Min
authors: M
authors: Jiang
authors: Wotang T
authors: WT
authors: Huang
authors: Yun
authors: Y
authors: Ling
authors: Steven H
authors: SH
authors: Olson
authors: Daqing
authors: D
authors: Sun
authors: Guifen
authors: G
authors: Xu
authors: Xuelei
authors: X
authors: Yan
authors: Bradley K
authors: BK
authors: Wong
authors: Lixia
authors: L
authors: Jin
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001682:Biological Availability; D001711:Biotransformation / Q000187:drug effects; D004285:Dogs; D020719:Glucuronides / Q000378:metabolism; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D010881:Piperidones / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: C588087:2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; D000085:Acetates; D020719:Glucuronides; D010881:Piperidones; D047428:Protein Kinase Inhibitors
keywords: AMG 232; clearance prediction; hepatocytes; in vivo–in vitro correlation; metabolism; p53–MDM2 inhibitor; pharmacokinetics