| Abstrakt: |
Aims: Our aim was to determine the absolute bioavailability, mass balance, metabolism and excretion of soticlestat (TAK‐935). Methods: An open‐label, two‐period, single‐site, phase 1 study was conducted in six healthy men. In Period 1, a single 300 mg dose of soticlestat was administered orally, followed by a 15‐min intravenous infusion of [14C]soticlestat 50 μg (~1 μCi) 10 min later. In Period 2, a single 300 mg dose (~100 μCi) of [14C]soticlestat in solution was administered orally. Samples were collected, analysed for radioactivity or unchanged soticlestat, and profiled for metabolites. Results: In Period 1, soticlestat had an absolute bioavailability of 12.6% (90% confidence interval, 7.81–20.23%). In Period 2, there was near‐complete recovery of total radioactivity (TRA) following a 300 mg dose of [14C]soticlestat: urine, 94.8% (standard deviation [SD], 1.35%); faeces, 2.7% (SD, 1.67%). Of TRA, 0.1% (SD, 0.09%) and 0.6% (SD, 0.21%) were recovered as soticlestat and metabolite M‐I in urine, respectively. In plasma, soticlestat and M‐I reached geometric mean maximum observed concentrations of 1352 ng/mL (geometric percent coefficient of variation [gCV%], 61.3) and 253.2 ng/mL (gCV%, 44.1) after 25 min and declined with mean terminal half‐lives (SD) of 5.7 (2.90) and 2.0 (0.15) h, respectively. Soticlestat represented 4.9% of TRA in plasma. Soticlestat was rapidly eliminated primarily via O‐glucuronidation to metabolite M3, which was the dominant species in plasma (92.6%) and urine (86%). Conclusions: This study indicates that soticlestat and its metabolites are rapidly cleared and eliminated, lowering the risk of dose accumulation from repeated dosing and supporting further investigation of soticlestat. [ABSTRACT FROM AUTHOR] |
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