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

Bioavailability Study of Stiripentol After Single Oral Administration of Two Different Formulations (Capsule and Oral Suspension) in 24 Healthy Subjects

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.

Inclusion Criteria

• Aged between 18 and 50 years (inclusive).
• Considered healthy after a comprehensive clinical assessment (medical history + complete physical exam).
• Body Mass Index (BMI) between 18 and 30 kg/m² (inclusive) and body weight ≥ 50 kg at screening.
• Normal blood pressure (BP) and heart rate (HR) after 10 minutes supine at screening : Systolic BP: 90-145 mmHg, Diastolic BP: 45-90 mmHg, HR: 40-90 bpm, Or values outside these ranges but judged not clinically significant (NCS) by the Investigator.
• Normal ECG at screening (10-min resting 12-lead ECG): PR interval: 110-210 ms, QRS interval : < 120 ms, QTcF interval: ≤ 450 ms, No evidence of sinus node dysfunction, Or values outside these ranges but judged NCS by the Investigator.
• Laboratory parameters within normal ranges (hematology, biochemistry, urinalysis); slight deviations allowed if not clinically relevant per Investigator.
• Women of non-childbearing potential, or women of childbearing potential using at least one acceptable contraceptive method throughout the study and 1 month after last treatment.
• Female subjects of childbearing potential: negative pregnancy test (serum or urine) at screening and Day 0.
• Covered by Health Insurance System and/or compliant with National Law requirements for biomedical research.
• Able and willing to comply with study requirements.
• Written informed consent obtained.

Exclusion Criteria

• Unsuitable veins for repeated venipuncture.
• Relevant history/presence of cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematological, neurological, psychiatric, systemic, or infectious disease.
• Evidence of any clinically significant acute or chronic disease.
• History of suicidal ideation or suicide attempt.
• Surgery (including clinical trial procedures) within 2 months before dosing.
• Blood donation within 2 months before dosing.
• History/presence of drug hypersensitivity, asthma, or allergy.
• Known hypersensitivity to study materials or related compounds.
• Inability/difficulty swallowing capsules.
• No possibility of emergency contact.
• Any drug intake (except paracetamol) within 4 weeks prior to dosing or < 5 half-lives (whichever longer). Prohibited: carbamazepine, phenytoin, phenobarbital, CYP enzyme modulators.
• Use of herbal products affecting CYP enzymes within 2 weeks or < 5 half-lives before dosing.
• Special diets (vegetarian, vegan, gluten-free).
• Vigorous exercise from 4 days before dosing until post-study assessments.
• Pregnant or breastfeeding women.
• Drug/alcohol abuse history, daily alcohol intake > 4 drinks, or positive alcohol test.
• Excessive xanthine beverages (> 5 cups/day).
• Nicotine use > 5 cigarettes/day or inability to abstain 48h before and during study.
• Intake of grapefruit/Seville oranges/poppy seed or other CYP modulators 1 week before dosing and during study.
• Intake of methylxanthines (coffee, tea, cola, cocoa, mate, guarana, chocolate) or quinine (e.g., tonic water) from 48h before dosing and during study.
• Unable/unwilling to follow diet requirements (see protocol section 10.7).
• Positive test for HBsAg, HCV antibody, or HIV 1/2.
• Positive drug screen.
• Significant biological or clinical abnormalities judged incompatible with study.
• Participation in another interventional trial during exclusion period or investigational product within last 60 days or < 5 half-lives.
• Under guardianship, curatorship, or deprived of liberty.
• Under Court protection.
• Would exceed €6000 compensation for biomedical research in last 12 months (including this study).
• Health status not allowing provision of informed consent.