Absorption, metabolism, and excretion of [<sup>14</sup>C]-sebetralstat (KVD900) following a single oral dose in healthy male participants
Creators: name: Mutch, Peter
name: Bashir, Mohammad
name: Jung, Bonnie
name: Yi, Ping
name: Iverson, Matt
Publisher: name: Taylor & Francis
Year: 2022
Subjects: subject: Biochemistry
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Physiology
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Ecology
subject: Immunology
subject: FOS: Clinical medicine
subject: Cancer
subject: Hematology
subject: Infectious Diseases
subject: FOS: Health sciences
subject: Virology

description: 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) [<sup>14</sup>C]-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.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 (<i>N</i>-des-pyridone-sebetralstat-carboxylic acid), M3 (pyridine <i>O</i>-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<sub>0–24</sub>), followed by relatively low proportions of metabolites: M19 (7.10%), M3 (4.01%), and M10 (4.00%). Although M19 was &gt;10% of the plasma radioactivity AUC<sub>0–24</sub>, in one participant it comprised a mean of &lt;10% of AUC<sub>0–24</sub>. Plasma levels of M19 were measured at the NOAEL dose in a rat toxicology study, where higher exposure was observed <i>vs.</i> that in humans.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. 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) [<sup>14</sup>C]-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. 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 (<i>N</i>-des-pyridone-sebetralstat-carboxylic acid), M3 (pyridine <i>O</i>-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<sub>0–24</sub>), followed by relatively low proportions of metabolites: M19 (7.10%), M3 (4.01%), and M10 (4.00%). Although M19 was &gt;10% of the plasma radioactivity AUC<sub>0–24</sub>, in one participant it comprised a mean of &lt;10% of AUC<sub>0–24</sub>. Plasma levels of M19 were measured at the NOAEL dose in a rat toxicology study, where higher exposure was observed <i>vs.</i> that in humans. 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.