Abstract

Two open-label, phase 1 studies (NCT05064449, NCT05098041) investigated the effects of cytochrome P450 (CYP) 3A inhibition (via itraconazole), UDP glucuronosyltransferase (UGT) 1A9 inhibition (via mefenamic acid), and CYP3A induction (via rifampin) on the pharmacokinetics of soticlestat and its metabolites M-I and M3. In period 1 of both studies, participants received a single dose of soticlestat 300 mg. In period 2, participants received itraconazole on days 1–11 and soticlestat 300 mg on day 5 (itraconazole/mefenamic acid study; part 1); mefenamic acid on days 1–7 and soticlestat 300 mg on day 2 (itraconazole/mefenamic acid study; part 2); or rifampin on days 1–13 and soticlestat 300 mg on day 11 (rifampin study). Twenty-eight healthy adults participated in the itraconazole/mefenamic acid study (14 per part) and 15 participated in the rifampin study (mean age, 38.1–40.7 years; male, 79–93%). For maximum observed concentration, the geometric mean ratios (GMRs) of soticlestat + itraconazole, mefenamic acid, or rifampin to soticlestat alone were 116.6%, 107.3%, and 13.2%, respectively, for soticlestat; 10.7%, 118.0%, and 266.1%, respectively, for M-I, and 104.6%, 88.2%, and 66.6%, respectively, for M3. For area under the curve from time 0 to infinity, the corresponding GMRs were 124.0%, 100.6%, and 16.4% for soticlestat; 13.3%, 117.0%, and 180.8% for M-I; and 120.3%, 92.6%, and 58.4% for M3. Soticlestat can be administered with strong CYP3A and UGT1A9 inhibitors, but not strong CYP3A inducers (except for antiseizure medications, which will be further evaluated in ongoing phase 3 studies). In both studies, all treatment-emergent adverse events were mild or moderate.

SIGNIFICANCE STATEMENT These drug–drug interaction studies improve our understanding of the potential changes that may arise in soticlestat exposure in patients being treated with CYP3A inhibitors, UGT1A9 inhibitors, or CYP3A inducers. The results build on findings from previously published soticlestat studies and provide important information to help guide clinical practice. Soticlestat has shown positive phase 2 results and is currently in phase 3 development for the treatment of seizures in patients with Dravet syndrome and Lennox–Gastaut syndrome.

Introduction

Dravet syndrome and Lennox–Gastaut syndrome are rare developmental and epileptic encephalopathies that are characterized by frequent seizures and developmental disability (Scheffer et al., 2017; Asadi-Pooya, 2018). Treatments for patients with Dravet syndrome or Lennox–Gastaut syndrome focus on reducing the frequency of the most incapacitating seizures (Asadi-Pooya, 2018; Strzelczyk and Schubert-Bast, 2022); however, resistance to antiseizure medications is common, and therapy with multiple antiseizure medications and changes to treatment over time are often needed to address patients’ individual needs. The concurrent use of multiple antiseizure medications can increase the risk of drug–drug interactions (DDIs) and potential adverse events (AEs), such as increased seizure frequency, and can deter adherence to treatment (de Leon, 2015; Verrotti et al., 2020). As such, new therapies are needed to improve tolerability and to decrease the risk of DDIs in patients with Dravet syndrome or Lennox–Gastaut syndrome (Resnick and Sheth, 2017; Strzelczyk and Schubert-Bast, 2022).

Soticlestat is a first-in-class inhibitor of cholesterol 24-hydroxylase (also known as the cytochrome P450 [CYP] enzyme CYP46A1) (Koike et al., 2022) that is in phase 3 development for the treatment of seizures in patients with Dravet syndrome or Lennox–Gastaut syndrome (ClinicalTrials.gov: NCT04940624; NCT04938427; NCT05163314). The pharmacokinetic (PK) properties of soticlestat have been characterized in various studies. Findings have shown that renal excretion of soticlestat is limited; less than 1% of administered soticlestat is recovered in urine and the mean renal clearance value for soticlestat is estimated to be 0.2 (standard deviation [S.D.], 0.11) L/h. The majority of soticlestat is rapidly metabolized by glucuronidation via UDP glucuronosyltransferases (UGTs) 2B4 (fraction metabolized: 81.2%) and 1A9 (fraction metabolized: 9.3%) to the glucuronide M3, and by oxidation via CYP3A4/5 to the aromatic N-oxide M-I (fraction metabolized: 9.5%), with M-I or M3 demonstrating negligible biologic activity compared with soticlestat (Yin et al., 2023). Plasma protein binding of soticlestat was found to be concentration dependent, ranging from 70.6% at 10 μg/ml to 94.0% at 0.1 μg/ml in vitro, while there is limited partitioning of soticlestat into blood cells, as demonstrated by mean whole blood:plasma partitioning ratios of 0.5–0.7 (Yin et al., 2023). Furthermore, soticlestat is highly soluble and highly permeable compared with a reference high permeability compound ([3H]propranolol). The clinical dose of 300 mg is soluble in 250 ml of aqueous media over the pH range of 1.2 to 6.8, while the permeability of soticlestat in Caco-2 cells from the apical to the basal side is 15.5 × 10−6 cm/s.

In humans, the majority of soticlestat is rapidly metabolized by glucuronidation via UDP glucuronosyltransferases (UGTs) 2B4 (fraction metabolized, 81.2%) and 1A9 (fraction metabolized, 9.3%) to the glucuronide M3, and by oxidation via CYP3A4/5 to the aromatic N-oxide M-I (fraction metabolized, 9.5%). Metabolites M-I and M3 demonstrate negligible biologic activity compared with soticlestat (Yin et al., 2023). Many medications are inhibitors or inducers of CYP3A, UGT1A9, or UGT2B4, including commonly prescribed antiseizure medications, and could affect the plasma exposure of soticlestat (de Leon, 2015). Consequently, identifying potential DDIs is important to ensure that soticlestat exposure remains within an acceptable range for efficacy and safety when administered with concomitant medications.

In phase 1 and 2 studies, soticlestat was well tolerated in healthy adults after single doses of up to 1350 mg and in healthy adults and patients with developmental and epileptic encephalopathies (including Dravet syndrome or Lennox–Gastaut syndrome) after multiple doses of up to 300 mg twice daily (Halford et al., 2021; Wang et al., 2021, 2022; Hahn et al., 2022).

To determine the extent of any potential changes to soticlestat exposure and to inform dose adjustment recommendations, we investigated and characterized the effects of strong CYP3A inhibition via itraconazole, strong CYP3A induction via rifampin, and strong UGT1A9 inhibition via mefenamic acid on the PK of soticlestat in healthy adults.

Materials and MethodsEthics

Both studies were conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice (E6) and the Declaration of Helsinki. All other ethics guidelines, applicable laws, and local regulations were followed. All study documents were approved by the Institutional Review Board or the Research Ethics Committee of the study site(s) before study initiation. All participants provided written informed consent.

Itraconazole and Mefenamic Acid StudyStudy Design and Dose Selection

This open-label, two-part, phase 1 study was conducted at a single site in the USA between October 2021 and November 2021 (ClinicalTrials.gov identifier: NCT05064449). Each part of the study was conducted as a two-period, fixed-sequence design (Supplemental Fig. 1A) and participants who enrolled in part 1 were independent from participants who enrolled in part 2. Dose selection for soticlestat was based on the maximum twice-daily dose (300 mg) that is under investigation in phase 3 studies (NCT04940624; NCT04938427; NCT05163314). Dose selection for itraconazole and mefenamic acid was based on clinical recommendations (Chen et al., 2019; FDA: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/015034s045lbl.pdf).

In part 1, soticlestat (Bushu Pharmaceuticals, Ltd., Saitama, Japan) was administered as a single 300 mg dose orally (three 100 mg tablets) on day 1 after an overnight fast of at least 10 hours, followed by a washout period of 4 days (period 1). Itraconazole 200 mg (Janssen Pharmaceutica NV, Beerse, Belgium) was then administered once daily as a solution on days 1–4 to achieve maximum CYP3A inhibition before soticlestat administration (Chen et al., 2019). On the morning of day 5, after an overnight fast of at least 10 hours, soticlestat was administered as a single 300 mg dose orally with itraconazole 200 mg. Itraconazole 200 mg was administered alone on days 6–11 to maintain CYP3A inhibition (period 2).

In part 2, soticlestat was administered as a single 300 mg dose orally (three 100 mg tablets) on day 1 after an overnight fast of at least 10 hours, followed by a washout period of 4 days (period 1). Mefenamic acid (Micro Laboratories Limited, Bangalore, India) was administered every 6 hours alone on day 1, with an initial dose of 500 mg in the morning; all subsequent doses were 250 mg. On the morning of day 2, mefenamic acid 250 mg was administered with soticlestat 300 mg after a fasting period of at least 6 hours, followed by mefenamic acid 250 mg alone on days 3–7 to maintain UGT1A9 inhibition (period 2).

In periods 1 and 2 of parts 1 and 2, blood samples for PK evaluation of soticlestat and its metabolites were collected before dose administration, and at 0.133, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 14, 24, 36, 48, 72, and 96 hours after dose administration. In period 2 of part 1, blood samples were collected at 120, 144, and 168 hours after soticlestat dose administration. In period 2 of part 2, blood samples were collected at 120 and 144 hours after soticlestat dose administration. Plasma concentrations of soticlestat, M-I, and M3 were determined by a validated sensitive and specific liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based method (API-5500 mass spectrometer; SCIEX, Framingham, MA, USA). The bioanalytical methods of soticlestat, M-I and M3 are described in the Supplemental Materials. A safety follow-up phone call was conducted within 13–17 days of the last soticlestat dose.

Study Participants

Eligible participants were healthy, male or female of non-childbearing potential, non-smoking adults aged 19–55 years, who had a body mass index (BMI) of 18.0–32.0 kg/m2. Key exclusion criteria included: any past or present clinically significant epilepsy, seizure, or convulsion, or tremor or related symptoms; any pre-existing conditions that may affect the absorption, distribution, metabolism, or elimination of the study drug; known or suspected poor CYP2C9 metabolizers based on previous history or experience with other CYP2C9 substrates (part 2 only, because mefenamic acid undergoes glucuronidation and is also metabolized by CYP2C9 to 3-hydroxymethyl mefenamic acid).

Study Objectives and Endpoints

The primary objective was to assess the effect of multiple doses of itraconazole and mefenamic acid on the single-dose PK of soticlestat. The secondary objective was to evaluate safety and tolerability of soticlestat following a single oral dose of soticlestat in the presence or absence of itraconazole, a strong CYP3A inhibitor, and mefenamic acid, a strong UGT1A9 inhibitor. The primary endpoints were maximum observed concentration (Cmax), area under the concentration–time curve from time 0 to infinity (AUC∞), and area under the concentration–time curve from time 0 to time of last quantifiable concentration (AUClast), and time of first occurrence of Cmax (tmax) for soticlestat alone compared with soticlestat administered with itraconazole or mefenamic acid. Exploratory endpoints included the PK parameters for metabolites. Safety assessments included the incidence of AEs, evaluation using the Columbia Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2011), electrocardiogram (ECG) assessments, vital signs, and laboratory tests. Treatment-emergent adverse events (TEAEs) were defined as AEs that were starting or worsening at the time of, or after, study drug administration. Each TEAE was attributed to a treatment, based on the onset date and time of the AE.

Data Analysis

The PK analysis population included all participants who adhered to the study protocol and had interpretable PK data. The safety analysis population included participants who received at least one dose of soticlestat or soticlestat + itraconazole or mefenamic acid. Fourteen participants were enrolled in part 1 and a further 14 participants were enrolled in part 2 to ensure that 12 participants completed each part of the study.

The effect of coadministration of itraconazole or mefenamic acid on key PK parameters (AUC∞, AUClast, Cmax) of soticlestat, M-I, and M3 was assessed by a linear mixed-effects model. The geometric mean ratios (GMRs) for the log-transformed PK parameters of soticlestat + itraconazole or mefenamic acid/soticlestat alone and associated 90% confidence intervals (CIs) were calculated with treatment as a fixed effect and participant as a random effect. The use of 90% CIs was based on clinical guidance (FDA: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/015034s045lbl.pdf). PK analyses were summarized descriptively by treatment and PK parameters by sample size (n); arithmetic mean and coefficient of variation (CV in per cent [CV%]); geometric mean and CV%; S.D.; standard error of the mean; minimum value; median value; and maximum value. A non-parametric analysis for paired samples (Wilcoxon signed-rank test) was used to analyze the tmax data for plasma soticlestat, M-I, and M3. The difference of medians (treatment effect) for soticlestat + itraconazole or mefenamic acid/soticlestat alone and the corresponding 90% CIs were estimated using the Hodges–Lehmann method and Walsh averages. The tmax values were not log-transformed.

All statistical analyses were performed using SAS software, version 9.4 (SAS Institute Inc, Cary, NC, USA). PK analyses were performed using Phoenix WinNonlin software, version 8.3 (Certara, Princeton, NJ, USA).

Rifampin StudyStudy Design and Dose Selection

This open-label, phase 1 study was conducted at a single site in Northern Ireland, UK, between November 2021 and March 2022 (ClinicalTrials.gov identifier: NCT05098041). The study was conducted as a two-period, fixed-sequence design (Supplemental Fig. 1B). Dose selection for soticlestat was based on the maximum twice-daily dose (300 mg) that is under investigation in phase 3 studies (NCT04940624; NCT04938427; NCT05163314). Dose selection for rifampin was based on clinical recommendations and similar DDI studies (Tortorici et al., 2014).

In period 1, soticlestat was administered as a single 300 mg dose orally (three 100 mg tablets) on day 1 under fasting conditions, followed by a washout period of 4 days. In period 2, rifampin 600 mg (two 300 mg capsules; Sanofi, Berkshire, UK) was administered once daily on days 1–13 under fasting conditions to achieve maximum CYP3A induction (Chen et al., 2019). On the morning of day 11, soticlestat was administered as a single 300 mg dose orally with the rifampin 600 mg dose.

PK blood samples for soticlestat and its metabolites were collected before dose administration in periods 1 and 2, and at 0.133, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 14, 24, 36, 48, 72, and 96 (period 1 only) hours after dose administration. The sample at 96 hours corresponded to the pre-dose sample for period 2. Plasma concentrations of soticlestat, M-I, and M3 were determined by a validated sensitive and specific liquid chromatography–tandem mass spectrometry-based method (full methods described in the Supplemental Materials). A safety follow-up phone call was conducted within 13–17 days of the last soticlestat dose.

Study Participants

Eligible participants were healthy, non-smoking adults aged 18–55 years who had a BMI of 18.0–32.0 kg/m2. Key exclusion criteria included: any past or present clinically significant epilepsy, seizure, or convulsion, or tremor or related symptoms; any pre-existing conditions that may affect the absorption, distribution, metabolism, or elimination of the study drug; and females of childbearing potential.

Study Objectives and Endpoints

The primary objective was to assess the effect of multiple doses of rifampin on the single-dose PK of soticlestat. The secondary objective was to evaluate safety and tolerability of soticlestat following a single oral dose in the presence or absence of rifampin, a strong CYP3A inducer. The primary endpoints were Cmax, AUC∞, AUClast, and tmax for soticlestat alone compared with soticlestat + rifampin. Exploratory endpoints included the PK parameters for the metabolites M-I and M3. Safety assessments included the incidence of TEAEs among participants, ECG assessments, vital signs, laboratory evaluations, and C-SSRS.

Data Analysis

The PK analysis population included all participants who adhered to the study protocol and had interpretable PK data. The safety analysis population included participants who received at least one dose of soticlestat or rifampin. In total, 14 participants were enrolled to ensure that at least 12 participants completed the study. A 15th participant was enrolled as a replacement for one participant who prematurely discontinued the study.

The effects of the coadministration of rifampin on key PK parameters (AUC∞, AUClast, Cmax) of soticlestat, M-I, and M3 were assessed by a linear mixed-effects model. The GMRs for the log-transformed PK parameters of soticlestat + rifampin/soticlestat alone and associated 90% CIs were calculated with treatment as a fixed effect and participant as a random effect. PK analyses were summarized descriptively by treatment and PK parameters by sample size (n); arithmetic mean and CV%; geometric mean and CV%; S.D.; standard error of the mean; minimum value; median value; and maximum value. A non-parametric analysis for paired samples (Wilcoxon signed-rank test) was used to analyze the tmax data for plasma soticlestat, M-I, and M3. The difference of medians (treatment effect) for soticlestat + itraconazole or MA/soticlestat alone and the corresponding 90% CI were estimated using the Hodges–Lehmann method and Walsh averages. The tmax values were not log-transformed.

All statistical analyses were performed using SAS software, version 9.4 (SAS Institute Inc, Cary, NC, USA). PK analyses were performed using Phoenix WinNonlin software, version 8.3 (Certara, Princeton, NJ, USA).

ResultsItraconazole and Mefenamic Acid StudyBaseline Demographics and Characteristics of Participants

All of the 28 enrolled healthy volunteers (14 per part) completed the study. For part 1, most participants were male (78.6%) and White (57.1%) and, for part 2, most were male (85.7%) and White (35.7%) or Black/African American (35.7%) (Table 1). The mean (S.D.) age was 40.7 (9.2) years for participants in part 1, with a mean (S.D.) weight of 80.2 (11.9) kg and a mean (S.D.) BMI of 26.3 (2.7) kg/m2. For participants in part 2, the mean (S.D.) age was 40.2 (8.3) years, the mean (S.D.) weight was 84.9 (12.2) kg, and the mean (S.D.) BMI was 28.9 (3.0) kg/m2.

TABLE 1

Baseline demographics

PK Analysis

Key PK parameters for soticlestat, M-I, and M3 (soticlestat ± itraconazole or MA) are presented in Table 2, with PK analysis summarized in Table 3. The GMRs for Cmax of soticlestat with itraconazole or mefenamic acid compared with soticlestat alone were 116.6% and 107.3%, respectively, for soticlestat; 10.7% and 118.0%, respectively, for M-I; and 104.6% and 88.2%, respectively, for M3. For AUC∞, the corresponding GMRs were 124.0% and 100.6%, respectively, for soticlestat; 13.3% and 117.0%, respectively, for M-I; and 120.3% and 92.6%, respectively, for M3. No statistical differences were observed in the tmax values between soticlestat with itraconazole or mefenamic acid and soticlestat alone (all P > 0.05). The mean soticlestat plasma concentration–time curves for both parts of the study were similar in the presence or absence of itraconazole or mefenamic acid, and are presented in Fig. 1, A and B, respectively (individual plots are provided in Supplemental Figs. 2 and 3).

TABLE 2

PK parameters of soticlestat, M-I, and M3 following itraconazole coadministration (part 1) in the itraconazole and mefenamic acid study

TABLE 3

Effects of itraconazole (part 1) or mefenamic acid (part 2) coadministration on the PK of soticlestat, M-I, and M3 in the itraconazole and M mefenamic acid A study

Fig. 1.

Soticlestat plasma concentration–time curves in the presence or absence of (A) itraconazole, (B) mefenamic acid, or (C) rifampin (semi-log scale).

Safety

In part 1, eight TEAEs were experienced by three participants (21.4%) (Table 4). The most frequently reported TEAE was nausea (n = 2, 14.3%). Seven TEAEs were mild in severity, and one was moderate (headache following itraconazole alone). The investigator considered three TEAEs to be related to itraconazole alone, three TEAEs to be related to soticlestat and itraconazole, and two TEAEs to be unrelated to soticlestat or itraconazole.

In part 2, 11 TEAEs were experienced by four participants (28.6%). None of the reported TEAEs occurred in more than one participant and all were mild in severity. The investigator considered four TEAEs to be related to soticlestat alone, two TEAEs to be related to mefenamic acid alone, and five TEAEs to be related to soticlestat and mefenamic acid.

There were no serious TEAEs, severe TEAEs, TEAEs leading to treatment discontinuation, or deaths. No trends were noted in physical examinations, vital signs, laboratory tests, C-SSRS results, or ECG data for participants during the study. No participants had an interruption or reduction in dosages during the study.

Rifampin StudyBaseline Demographics and Characteristics of Participants

Of the 15 healthy volunteers who were enrolled in the study and received the study drug(s), 14 completed the study. One participant discontinued the study early after withdrawing their consent to participate on day 1 of period 1 owing to personals reasons and another participant was enrolled as a replacement. Most participants were male (93%) and all were White (Table 1). The mean (S.D.) age of participants was 38.1 (10.1) years, with a mean (S.D.) weight of 80.7 (10.2) kg and a mean (S.D.) BMI of 26.7 (3.2) kg/m2.

PK Analysis

Key PK parameters for soticlestat, M-I, and M3 (soticlestat ± rifampin) are summarized in Table 5, with PK analysis presented in Table 6. The GMR of soticlestat with rifampin compared with soticlestat alone for Cmax was 13.2% for soticlestat, 266.1% for M-I, and 66.6% for M3. For AUC∞, the corresponding GMR was 16.4% for soticlestat, 180.8% for M-I, and 58.4% for M3. No statistical difference was observed in the tmax value between soticlestat with rifampin compared with soticlestat alone (P > 0.05). The mean soticlestat plasma concentration–time curve demonstrates that soticlestat exposure is reduced in the presence of rifampin compared with soticlestat alone (Fig. 1; individual plots are provided in Supplemental Fig. 4).

TABLE 5

PK parameters of soticlestat, M-I, and M3 in the rifampin study

TABLE 6

Effect of rifampin coadministration on the PK of soticlestat, M-I, and M3 in the rifampin study

Safety

Nine TEAEs were experienced by four participants (26.7%) (Table 4). None of the reported TEAEs occurred in more than one participant and all were mild or moderate in severity. The investigator considered two TEAEs to be related to rifampin and all other TEAEs to be unrelated to soticlestat or itraconazole. There were no serious TEAEs, severe TEAEs, TEAEs leading to treatment discontinuation, or deaths. No trends were noted in physical examinations, vital signs, laboratory tests, C-SSRS results, or ECG data for participants during the study. No participants had an interruption or reduction in dosages during the study.

Discussion

Based on the negligible effects of itraconazole or mefenamic acid on soticlestat PK, the potential for a clinically important DDI between soticlestat and CYP3A or UGT1A9 inhibitors is low. However, strong CYP3A inducers are not recommended to be administered with soticlestat, given the substantial and potentially clinically significant reduction in overall and peak exposure of soticlestat when administered with rifampin (AUC∞, –84%; AUClast, –85%; Cmax, –87%). Antiseizure medications that are CYP3A inducers (such as carbamazepine, phenobarbital, phenytoin, oxcarbazepine, and clobazam) (de Leon, 2015) constitute an exception because they have not been found to affect the total plasma exposure of soticlestat in phase 2 studies. Administration of soticlestat with antiseizure medications that are CYP3A inducers will be further monitored in ongoing phase 3 studies, and population PK analyses will be performed to evaluate the impact of these antiseizure medications on soticlestat exposure upon study completion. Given the polytherapy approach to treating patients with Dravet syndrome or Lennox–Gastaut syndrome, dose adjustments will be specific to individuals if a DDI should occur. The findings from the present studies were used to inform protocol development for the subsequent phase 2 and phase 3 studies.

Findings from these two DDI studies support CYP3A as an important metabolic pathway for soticlestat (Yin et al., 2023). CYP3A inhibition by itraconazole had minimal effects on the PK of soticlestat and the glucuronide of soticlestat, M3, but reduced the levels of the aromatic N-oxide of soticlestat, M-I. Conversely, CYP3A induction by rifampin substantially affected the PK of soticlestat, resulting in a large decrease in AUC and Cmax for soticlestat that was accompanied by a substantial increase in M-I levels and a moderate decrease in M3 levels. Although UGT1A9 inhibition by mefenamic acid had little to no effect on the PK of soticlestat, a slight increase in M-I was observed alongside a comparable decrease in M3. Overall, the increase in M-I levels following CYP3A induction indicates that metabolism of soticlestat via CYP3A can become dominant, despite glucuronidation to M3 representing the major metabolic pathway for soticlestat (Yin et al., 2023).

After a 7-day course of itraconazole and a single 300 mg dose of soticlestat, the overall exposure of soticlestat was minimally increased (AUC∞, 24% and AUClast, 22%) in the presence of itraconazole, while Cmax was only 17% higher with soticlestat + itraconazole. Although PK parameters for M3 were not increased considerably, the exposure of M-I was greatly reduced by itraconazole coadministration. However, given that M-I is not considered an active metabolite, and changes to soticlestat exposure were minimal, none of the effects of itraconazole were considered clinically meaningful. Therefore, the risk of a DDI when soticlestat is coadministered with CYP3A inhibitors is very low.

In part 2 of the itraconazole and mefenamic acid study, following a 7-day course of mefenamic acid and a single 300 mg dose of soticlestat, the overall and peak exposures of soticlestat were very minimally increased (AUC∞, 1%; AUClast, 7%; Cmax, 7%) and M-I exposure also showed minimal increases (AUC∞, 17%; AUClast, 20%; Cmax, 18%). M3 exposure was minimally reduced (AUC∞, -7%; AUClast, -8%; Cmax, -12%) after coadministration of the UGT1A9 inhibitor mefenamic acid. Given that glucuronidation was found to be the major metabolic pathway for soticlestat in a mass balance study, these results suggest that soticlestat can be metabolized to M3 by other UGTs (such as UGT2B4) in the absence of UGT1A9 (Yin et al., 2023). Similarly to M-I, M3 is not considered an active metabolite.

The effects of mefenamic acid on the PK of soticlestat or its main metabolites were not considered to be clinically meaningful, given that soticlestat exposure was hardly affected by UGT1A9 inhibition. Therefore, the risk of a DDI when soticlestat is coadministered with UGT1A9 inhibitors is very low. Many commonly prescribed antiseizure medications demonstrate inhibitory activity toward UGTs, including valproate, lamotrigine, and clobazam (de Leon, 2015). These results provide reassurance that soticlestat exposure is likely to be unchanged and remain in a therapeutic range when coadministered with UGT1A9 inhibitors. Although soticlestat is primarily metabolized by UGT2B4, currently there is no specific and potent UGT2B4 inhibitor known to evaluate the effect of UGT2B4 inhibition on soticlestat exposure. Furthermore, it was not possible to investigate the effect of UGT induction due to the lack of specific and potent UGT inducers. However, rifampin has been reported to induce UGT2B4 and UGT1A9 in human hepatocytes (Soars et al., 2004; Gufford et al., 2018), possibly suggesting the minimal increase in M3 exposure observed in the rifampin study could be related to rifampin’s effect on UGT enzyme induction.

All AEs were mild or moderate when soticlestat was administered alone or with itraconazole, mefenamic acid, or rifampin. Of the few AEs that were considered by the investigator to be related to soticlestat, all were mild. Overall, safety findings were consistent with those from previous studies in healthy volunteers and patients with developmental and epileptic encephalopathies, including Dravet syndrome and Lennox–Gastaut syndrome. In all previous studies, AEs were mostly mild or moderate, especially for soticlestat doses equal to or below the maximum twice-daily dose (300 mg) under investigation in phase 3 studies. In the present study, TEAEs occurred at similar rates across study parts and treatment groups, which is also aligned with findings from previous studies (Halford et al., 2021; Wang et al., 2021, 2022; Hahn et al., 2022; Yin et al., 2023).

In conclusion, soticlestat can be coadministered with strong CYP3A and UGT1A9 inhibitors. To ensure that soticlestat exposure remains within an acceptable range for efficacy, soticlestat is not recommended to be coadministered with strong CYP3A inducers (except for antiseizure medications, such as carbamazepine, phenobarbital and phenytoin, which did not affect soticlestat plasma total exposure in phase 2 studies). These findings were used to inform protocol development for subsequent phase 3 studies in patients with Dravet syndrome and Lennox–Gastaut syndrome taking CYP3A inhibitors or inducers or UGT1A9 inhibitors, and in those initiating treatment with CYP3A inhibitors or inducers or UGT1A9 inhibitors. In both DDI studies, soticlestat was well tolerated when administered with and without itraconazole, mefenamic acid, or rifampin as evidenced by evaluation of AEs, laboratory tests, vital signs, C-SSRS results, and ECG data.

Acknowledgments

The authors would like to thank the principal investigators Allen Hunt and Devinda Weeraratne and the study participants. Under the direction of the authors and funded by Takeda Pharmaceutical Company Limited, R. Huntly and A. Jones of Oxford PharmaGenesis, Oxford, UK, provided writing assistance for this publication, in compliance with current Good Publication Practice guidelines. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by Oxford PharmaGenesis.

Data Availability

The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants data supporting the results reported in this article will be made available within three months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.

Authorship Contributions

Participated in research design: Yin, Dong, Stevenson, Lloyd, Petrillo, Baratta, Hui, Han.

Performed data analysis: Yin, Dong, Stevenson, Lloyd, Petrillo, Baratta, Hui, Han.

Wrote or contributed to the writing of the manuscript: Yin, Dong, Stevenson, Lloyd, Petrillo, Baratta, Hui, Han.

FootnotesReceived August 16, 2023.Accepted December 6, 2023.

This study was funded by the sponsor, Takeda Pharmaceutical Company Limited.

W.Y., C.D., A.S., V.L., M.B., T.H., and S.H. are employees of Takeda Pharmaceuticals USA, Inc., and stockholders of Takeda Pharmaceutical Company Limited. M.P. is a former employee of Takeda Pharmaceutical Company Limited and has nothing to disclose.

Previously presented at the American Epilepsy Society Annual Meeting, December 2–6, 2022, Nashville, TN, USA.

dx.doi.org/10.1124/dmd.123.001444.

↵This article has supplemental material available at dmd.aspetjournals.org.

AbbreviationsAEadverse eventAUC∞area under the concentration–time curve from time 0 to infinityAUCextrap%area under the concentration–time curve from last quantifiable concentration to infinity expressed as a percentageAUClastarea under the concentration–time curve from time 0 to time of last quantifiable concentrationBMIbody mass indexC-SSRSColumbia Suicide Severity Rating ScaleCH24Hcholesterol 24-hydroxylaseCIconfidence intervalCmaxmaximum observed concentrationCYPcytochrome P450DDIdrug–drug interactionGMRgeometric mean ratioPKpharmacokineticsTEAEtreatment-emergent adverse eventtmaxtime of first occurrence of maximum observed concentrationUGTUDP glucuronosyltransferaseCopyright © 2024 by The Author(s)