Investigation of the absolute bioavailability, mass balance, metabolism, and excretion of the cholesterol 24‐hydroxylase inhibitor soticlestat in healthy volunteers

Abstract

AbstractAimsOur aim was to determine the absolute bioavailability, mass balance, metabolism and excretion of soticlestat (TAK‐935).MethodsAn 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.ResultsIn 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%).ConclusionsThis 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.