Absolute Bioavailability and Mass Balance of the CH24H Inhibitor Soticlestat in Healthy Volunteers
Abstract number :
3.295
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2022
Submission ID :
2204915
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Mahnaz Asgharnejad, PharmD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Wei Yin, PhD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; T. Eric Ballard, PhD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Xiaochun Zhu, PhD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Samuel Hsiao, PhD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Annette Stevenson, MS – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Tom Hui, MD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Allen Hunt, MD – Celerion, Lincoln, NE, USA; Steve Han, MD, PhD – Takeda Development Center Americas, Inc, Cambridge, MA, USA
Rationale: Soticlestat (TAK-935) is a first-in-class inhibitor of cholesterol 24-hydroxylase (CH24H) in phase 3 development for treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). This study (ClinicalTrials.gov identifier: NCT04992442) was undertaken to determine the absolute bioavailability (ABA) and mass balance of soticlestat.
Methods: An open-label, fixed-sequence, single-site phase 1 study was conducted in healthy male volunteers, aged 19–55 years, weighing ≥50 kg and with a BMI of ≥18 and < 32 kg/m2. The study consisted of 2 treatment periods separated by an 8-day washout. In Period 1, a single oral 300 mg dose of soticlestat was administered followed after 10 mins by a 15-min intravenous infusion of 50 µg (~1 µCi) [14C]soticlestat. In Period 2, a single 300 mg oral dose (~100 µCi) of [14C]soticlestat in solution was administered. Blood, urine and fecal samples were collected for up to 8 and 11 days post-dose in Period 1 and Period 2, respectively. Primary objectives included the ABA of soticlestat in Period 1, the mass balance of [14C]soticlestat in Period 2 and the pharmacokinetics (PK) of [14C]soticlestat, M-I (an N-oxide metabolite of soticlestat) and total radioactivity (TRA) in Period 2. Secondary objectives included the PK and mass balance of soticlestat in Period 1 and metabolic profiles in Period 2.
Results: Six participants were enrolled. All completed the study and were included in the analysis set. In Period 1, soticlestat had an ABA of 12.57% (90% confidence interval, 7.81%, 20.23%) and mean maximum observed concentration (Cmax), median time to Cmax (tmax) and mean terminal half-life (t1/2z) values of 822.8 ng/mL, 1.1 h, and 4.1 h in plasma, respectively, following a 300 mg oral dose of soticlestat (Table 1). Mean concentration for [14C]soticlestat (50 µg) at the end of infusion (Ceoi) and t1/2z values were 2472 pg/mL and 3.0 h and the majority of TRA was recovered in excreta (urine: 95.2%, feces: 1.6%), with < 1% recovered as unchanged soticlestat. In Period 2, there was near complete recovery of TRA within 120 h of the 300 mg [14C]soticlestat dose (urine: 94.8%, feces: 2.7%), with 0.13% and 0.60% recovered as soticlestat or M‑I in urine, respectively. In plasma, both soticlestat and M-I had a median tmax of 0.42 h and, after reaching mean Cmax values of 1352 ng/mL and 253.2 ng/mL, declined with mean t1/2z values of 5.7 h and 2.0 h, respectively (Table 1). Overall, soticlestat represented 4.9% of TRA in plasma, while metabolite M3 (a glucuronide conjugate of soticlestat) was dominant in plasma (92.6%) and urine (86%).
Conclusions: Soticlestat is quickly absorbed and metabolized, with an ABA of 12.57%. Glucuronidation of soticlestat to M3 represents the major metabolic pathway, followed by renal elimination. 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 for the treatment of DS and LGS.
Funding: Takeda Pharmaceutical Company Limited
Anti-seizure Medications