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 ¹⁴C-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.

• AMG 232
• clearance prediction
• hepatocytes
• in vivo–in vitro correlation
• metabolism
• p53–MDM2 inhibitor
• pharmacokinetics

Acknowledgements

The authors thank Dr. Tim Carlson for providing careful review of the manuscript, Craig Uyeda and Stacy Fide for technical support with the in vivo mouse and rat studies, Sarah Wortman for formulation support, Dr. Brian M. Fox for the synthetic method of [¹⁴C]AMG 232, Michael Gribble, Dr. Zhihong Li and the Department of Medicinal Chemistry, Amgen (South San Francisco, CA) for providing AMG 232 synthetic standards.

Declaration of interest

The authors were all employed by Amgen, Inc. at the time this work was conducted.