Absorption, metabolism, and excretion of [¹⁴C]-sebetralstat (KVD900) following a single oral dose in healthy male participants

Abstract

1. Sebetralstat is an investigational oral plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema. Six healthy male participants received one dose of 600 mg (540 µCi) [¹⁴C]-sebetralstat. Plasma concentrations of sebetralstat and levels of total radioactivity in plasma, urine, and faeces were determined. Metabolite profiles of radioactivity were generated, and major metabolites structurally characterised.

2. Radioactivity was rapidly absorbed and was excreted with a mean of 95.8% (63.4% faeces; 32.4% urine) recovered by 216 h. Sebetralstat was the major drug-related component in urine and faeces, although metabolism predominated overall (main metabolites: M19 (des-[methoxy-fluoro-methylpyridine]-sebetralstat), M10 (N-des-pyridone-sebetralstat-carboxylic acid), M3 (pyridine O-desmethyl-sebetralstat), and M34 (pyridine dioxy-dihydro-sebetralstat)). Sebetralstat was the main radiolabelled component in plasma (mean of 64.1% of the total radioactivity AUC_0–24), followed by relatively low proportions of metabolites: M19 (7.10%), M3 (4.01%), and M10 (4.00%). Although M19 was >10% of the plasma radioactivity AUC_0–24, in one participant it comprised a mean of <10% of AUC_0–24. Plasma levels of M19 were measured at the NOAEL dose in a rat toxicology study, where higher exposure was observed vs. that in humans.

3. Given these findings and the lack of pharmacological activity of M19, it was concluded that there was no unique or disproportionate circulating metabolite in humans.

Keywords:

• Drug absorption
• drug excretion
• drug metabolism
• hereditary angioedema
• plasma kallikrein inhibitor
• sebetralstat

Acknowledgements

Medical writing assistance was provided under the direction of the authors by Lisa Baker, Ph.D., and Michael Howell, Ph.D., of Cadent, a Syneos Health group company, and was supported by KalVista Pharmaceuticals, Inc.

Author contributions

Mutch P. and Iverson M. participated in the research design. Bashir M., Jung B., and Yi P. conducted experiments. Mutch P., Bashir M., Jung B., Yi P., and Iverson M. performed data analysis and wrote or contributed to the writing of the manuscript.

Disclosure statement

PJM and MI are employees of KalVista Pharmaceuticals, Inc. BJ, MB, and PY have nothing to disclose.

Data availability statement

Reasonable requests for access to data will be considered and should be addressed to the corresponding author.

Additional information

Funding

The study was supported by KalVista Pharmaceuticals Ltd.