Absorption, metabolism and excretion of [¹⁴C]omarigliptin, a once-weekly DPP-4 inhibitor, in humans

Abstract

1. Omarigliptin (MARIZEV®) is a once-weekly DPP-4 inhibitor approved in Japan for the treatment of type 2 diabetes. The objective of this study was to investigate the absorption, metabolism and excretion of omarigliptin in humans.

2. Six healthy subjects received a single oral dose of 25 mg (2.1 μCi) [¹⁴C]omarigliptin. Blood, plasma, urine and fecal samples were collected at various intervals for up to 20 days post-dose. Radioactivity levels in excreta and plasma/blood samples were determined by accelerator mass spectrometry (AMS).

3. [¹⁴C]Omarigliptin was rapidly absorbed, with peak plasma concentrations observed at 0.5–2 h post-dose. The majority of the radioactivity was recovered in urine (∼74.4% of the dose), with less recovered in feces (∼3.4%), suggesting the compound was well absorbed.

4. Omarigliptin was the major component in urine (∼89% of the urinary radioactivity), indicating renal excretion of the unchanged drug as the primary clearance mechanism. Omarigliptin accounted for almost all the circulating radioactivity in plasma, with no major metabolites detected.

5. The predominantly renal elimination pathway, combined with the fact that omarigliptin is not a substrate of key drug transporters, suggest omarigliptin is unlikely to be subject to pharmacokinetic drug-drug interactions with other commonly prescribed agents.

Keywords:

• Accelerator mass spectrometry
• DPP-4 inhibitor
• human ADME
• omarigliptin
• once weekly
• target-mediated drug disposition

Acknowledgements

The authors want to thank the following individuals, all of MRL: Ashley Martucci and Michelle Groff for providing bioanalytical support for the study, Nicole Trainor for conducting the P-gp experiment, and Drs. Dan Cui and Mark Wirth for helpful discussions. The authors also wish to acknowledge Drs. Qi Song and Ali Arjomand at Accium BioSciences, Inc. (Seattle, WA) for providing AMS analysis, and the clinical staff at Charles River Clinical Services Northwest, Inc (formerly known as Comprehensive Clinical Development) for conducting the clinical study.

Declaration of interest

Authors were employees of Merck Sharp & Dohme Corp., Whitehouse Station, NJ USA, and potentially owned stock/held stock options of the company at the time of the study.

Supplementary material available online