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. (August 2015)

• Record Type: Journal Article
• Authors: Ye, Qiuping; Jiang, Min; Huang, Wotang T.; Ling, Yun; Olson, Steven H.; Sun, Daqing; Xu, Guifen; Yan, Xuelei; Wong, Bradley K.; Jin, Lixia
• Is Part Of: Xenobiotica. Volume 45:Number 8(2015:Aug.)
• Page Start: 681
• Page End: 692
• Publication Date: 2015-08
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2015.1010632
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>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 <italic>in vivo</italic> and <italic>in vitro</italic>, and in humans <italic>in vitro</italic>, and to predict its pharmacokinetics in humans through integrating PKDM data.</p> <p>2. AMG 232 exhibited low clearance (&lt;0.25 × Qh) and moderate to high oral bioavailability in mice, rats and monkeys (&gt;42%), but high clearance (0.74 × Qh) and low oral exposure in dogs (18%).</p> <p>3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered ¹⁴C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by <italic>in vivo</italic> rat studies and <italic>in vitro</italic> hepatocyte incubations in multiple species.</p> <p>4. The <italic>in vitro–in vivo</italic> 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.</p> </abstract>