Abstracts

Rationale: Soticlestat is a first-in-class inhibitor of cholesterol 24-hydroxylase (CH24H) in phase 3 development for treatment of Lennox-Gastaut syndrome and Dravet syndrome (NCT04940624; NCT04938427; NCT05163314). In vitro studies have shown that soticlestat is metabolized by oxidation (via CYP3A4) to M-I and glucuronidation (via UGT1A9 and 2B4) to M3. Two studies have assessed the effects of itraconazole (strong CYP3A inhibitor), mefenamic acid (MA; strong UGT1A9 inhibitor) and rifampicin (strong CYP3A inducer) on the pharmacokinetics (PK) of soticlestat.

Methods: Both studies were open-label, phase 1 studies conducted in healthy volunteers. Study 1 consisted of two parts with 2-period, fixed-sequence designs. Study 2 had a 2-period, fixed-sequence design. In Period 1 of both studies, participants received a single oral 300 mg soticlestat dose followed by a 4-day washout. In Period 2, participants received oral itraconazole on days 1–11 and a single 300 mg dose of soticlestat on the morning of day 5 (Study 1; Part 1); mefenamic acid from days 1–7 and a single 300 mg dose of soticlestat on the morning of day 2 (Study 1; Part 2) or oral rifampicin from days 1–13 and a single 300 mg dose of soticlestat on the morning of day 11 (Study 2). Blood samples were routinely collected to determine levels of soticlestat and its metabolite. The primary endpoints were maximum observed concentration (C_max), area under the concentration time curve from time 0 to infinity (AUC_∞) and to time of last quantifiable concentration (AUC_last), and time of first occurrence of C_max (t_max) for soticlestat alone vs soticlestat + itraconazole, MA or rifampicin. Exploratory endpoints were the PK parameters for metabolites.

Results: Twenty-eight healthy volunteers participated in Study 1 (14 per part) and 15 participated in Study 2. Preliminary PK results for soticlestat and M-I in Study 1 (soticlestat ± itraconazole or MA) and Study 2 (soticlestat ± rifampicin) are summarized in Tables 1 and 2, respectively. Geometric mean ratios (GMRs) of soticlestat + itraconazole, MA or rifampicin to soticlestat alone for C_max were 116.6%, 107.3% and 13.2%, respectively, for soticlestat, and 10.7%, 118.0% and 266.1%, respectively, for M-I. For AUC_∞, the corresponding GMRs were 124.0%, 100.6% and 16.4% for soticlestat and 13.3%, 117.0% and 180.8% for M-I, respectively.

Conclusions: Strong CYP3A and UGT1A9 inhibitors had little effect on the PK of soticlestat and therefore allowed for co-administration with soticlestat. Soticlestat plasma levels decreased with a strong CYP3A inducer and therefore strong CYP3A inducers should not be co-administered with soticlestat, except for antiseizure medications (as shown in the phase 2 program and to be confirmed in the phase 3 program). Identifying potential drug-drug interactions is important to ensure that soticlestat exposure remains within an acceptable range for efficacy and safety when administered with concomitant medications.

Funding: Studies funded by Takeda Pharmaceutical Company Limited.