Absorption, distribution, metabolism and excretion of an isocitrate dehydrogenase-2 inhibitor enasidenib in rats and humans

Abstract

1. The absorption, distribution, metabolism and excretion of enasidenib were studied following a single oral dose of [¹⁴C]enasidenib to rats (10 mg/kg; 100 μCi/kg) and healthy volunteers (100 mg; 318 nCi).

2. Enasidenib was readily absorbed, extensively metabolized and primarily eliminated via the hepatobiliary pathway. Enasidenib-derived radioactivity was widely distributed in rats. Excretion of radioactivity was approximately 95–99% of the dose from rats in 168 h post-dose and 82.4% from human volunteers in 504 h post-dose. In rat bile, approximately 35–42% of the administered dose was recovered, with less than 5% of the dose excreted as the parent drug. Renal elimination was a minor pathway, with <12% of the dose excreted in rat urine and <10% of the dose excreted in human urine.

3. Enasidenib was the prominent radioactive component in rat and human systemic circulation. Enasidenib was extensively metabolized in rats and human volunteers through N-dealkylation, oxidation, direct glucuronidation and combinations of these pathways. Glucuronidation was the major metabolic pathway in rats while N-dealkylation was the prominent metabolic pathway in human volunteers. All human metabolites were detected in rats.

Keywords:

• Absorption
• accelerator mass spectrometry
• distribution
• isocitrate dehydrogenase inhibitor
• metabolism and excretion
• species comparison

Acknowledgements

The authors would like to thank Gondi Kumar for his guidance to the studies and review of the manuscript, and thank QPS, LLC and Covance, Inc., for their contribution to the in-life phase of the studies.

Declaration of interest

This work was funded by Celgene Corporation. All authors are employees for Celgene Corporation, or its codeveloper Agios Pharmaceuticals.

Supplementary material available online