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

Abstract

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 [¹⁴ C]soticlestat 50 μg (~1 μCi) 10 min later. In Period 2, a single 300 mg dose (~100 μCi) of [¹⁴ C]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 [¹⁴ C]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.

Keywords: absorption; bioavailability; drug metabolism; epilepsy; excretion; pharmacokinetics.