Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice

Abstract

1. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity – attributable to metabolites formed by cytochrome P450 enzymes – but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs.

2. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate(s) were investigated in control and humanized-liver mice. Following oral administration of pomalidomide (100 mg/kg), plasma concentrations of 7-hydroxypomalidomide and 5-hydroxypomalidomide glucuronide were slightly higher in humanized-liver mice than in control mice.

3. Simulations of human plasma concentrations of pomalidomide were achieved with simplified physiologically-based pharmacokinetic models in both groups of mice in accordance with reported pomalidomide concentrations after low dose administration in humans.

4. The results indicate that pharmacokinetic profiles of pomalidomide were roughly similar between control mice and humanized-liver mice and that control and humanized-liver mice mediated pomalidomide 5-hydroxylation in vivo. Introducing one aromatic amino group into thalidomide resulted in less species differences in in vivo pharmacokinetics in control and humanized-liver mice.

Keywords:

• PBPK modeling
• pomalidomide
• TK-NOG mice

Acknowledgements

The authors thank Drs. Miyuki Kuronuma, Shotaro Uehara and Norie Murayama for their technical assistance.

Declaration of interest

The authors state that there are no interests to declare. The authors alone are responsible for the content and writing of the article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported in part by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research 26460206 (H.Y.) and National Institutes of Health grant R01 GM118122 (F.P.G.).