Bioavailability of Stiripentol After Single Oral Dose of Capsule vs Suspension in Healthy Subjects (STILIQ)

Overview

This is a Phase I, open-label, randomized, single-center, two-way cross-over study evaluating the relative bioavailability, pharmacokinetics, safety, and palatability of two formulations of stiripentol (Diacomit®), indicated in Dravet syndrome. The investigational products are 500 mg capsules (reference) and a 50 mg/mL oral suspension (test). The primary objective is to compare the relative bioavailability of the two formulations after a single 1,000 mg oral dose under fed conditions, based on Cmax, AUC0-t, and AUC0-∞. Secondary objectives include other PK parameters (tmax, tlag, ke, t1/2) and characterization of metabolites MIa and MIb. Palatability of the suspension will be assessed by questionnaire. Safety evaluation will include adverse events, laboratory tests, ECGs, urinalysis, drug and alcohol screening, serology, and vital signs. Twenty-four healthy volunteers (18-50 years) will be enrolled. Eligibility: BMI 18-30 kg/m², weight ≥50 kg, normal ECG and labs, and informed consent. Women of childbearing potential must use effective contraception and test negative for pregnancy. Exclusions: significant disease, recent surgery or blood donation, hypersensitivity, difficulty swallowing, use of CYP modulators (e.g., carbamazepine, grapefruit, herbal products), drug or alcohol abuse, smoking \>5 cigarettes/day, or inability to follow dietary restrictions. Subjects testing positive for HIV, HBV, HCV, or drugs of abuse will also be excluded. Each participant will attend a screening visit within 28 days before dosing, then two 3-day hospitalizations separated by a 7-15-day washout. On Day 1 of each period, they will receive either two capsules (1,000 mg) or 20 mL suspension (1,000 mg). Blood will be collected at 36 timepoints (≈180 mL total) for PK assessment. The total study duration per subject is about seven weeks, including screening, hospitalization, dosing, washout, and follow-up. Treatment consists of one dosing day per period. Sample size was based on prior data: 21 pairs provide 80% power for bioequivalence within 0.80-1.25 bounds; 24 subjects will be recruited to account for dropouts. Analyses will include the Safety Set, PK Concentrations Set, and PK Analysis Set. This trial aims to establish whether the oral suspension provides a PK profile comparable to capsules, while generating safety, tolerability, and palatability data to support a more convenient formulation for Dravet syndrome patients.

Stiripentol (Diacomit®) is currently marketed in two dosage forms: capsules (250 and 500 mg) and powder for oral suspension in sachets (250 and 500 mg). The powder formulation was developed for patients unable to swallow capsules. A previous study in healthy volunteers demonstrated that the capsule and sachet formulations were bioequivalent in terms of AUC but not Cmax. The Cmax of the sachet formulation was approximately 23% higher than that of the capsule, outside the accepted bioequivalence range. As a result, clinical supervision is recommended when switching between capsule and sachet formulations. According to the European Summary of Product Characteristics (SmPC), stiripentol dosage escalation should be gradual, starting at 20 mg/kg/day and increasing stepwise depending on age. Dravet syndrome typically begins in infancy, and early initiation of antiepileptic treatment is recommended. A new oral suspension formulation (50 mg/mL) has been developed to facilitate flexible dose adjustments and accurate administration in pediatric patients, especially infants, where precise titration is essential. This clinical study aims to compare the relative bioavailability of the new oral suspension (test formulation) to the capsule (reference formulation) after a single 1,000 mg dose under fed conditions. In addition to pharmacokinetic endpoints, safety, tolerability, and palatability will be assessed in healthy volunteers. The results will provide critical information on whether the new suspension offers a pharmacokinetic profile comparable to the capsule while improving dosing flexibility and patient convenience in clinical practice.