Pharmacokinetic Parameters of Stiripentol in Renal Impaired Patients and Matching Controls With Normal Renal Function

Inclusion Criteria:

Inclusion criteria for all subjects

Subjects/patients will be required to satisfy all the following inclusion criteria to be included in the study:

1. Male or female subjects, aged 18 to 80 years inclusive,

2. Females participating in this study must be of non-childbearing potential or usinghighly effective contraception for the full duration of the study and for 1 monthafter the end of treatment,

3. Negative serum pregnancy test at screening and urinary pregnancy test at Day -1 (ifapplicable),

4. A negative antigen test for Coronavirus Disease 19 (COVID 19),

5. Normal hepatic function (AST < 3xULN (Upper limit normal), ALT (Alanineaminotransferase); <1.5 ULN; bilirubin),

6. Non-smoker subject or smoker of not more than 5 cigarettes a day,

7. Signing a written informed consent in their native language prior to selection,

Additional inclusion criteria for renally impaired patients

Patients with renal impairment will be required to satisfy all the following inclusion criteria to be included in the study:

1. Documented renal impairment indicated by reduced RF at least 12 months of screeningor longer,

2. Stable renal function (eGFR) as evidenced by ≤ 30% difference in two evaluations ofRenal function (RF) on two separate occasions separated by at least 28 days with onemeasurement being the value at screening,

3. Renal impairment within the following ranges (using the Modification of Diet inRenal Disease-4 (MDRD4) equation) at screening:

4. mild renal impairment with eGFR ≥ 60 to < 90 mL/min/1.73 m²,

5. moderate renal impairment with eGFR ≥ 30 to < 60 mL/min/1.73 m²,

6. severe renal impairment with eGFR < 30 mL/min/1.73 m² and not on dialysis,

7. Supine blood pressure (BP) ≤ 180/104 mmHg,

8. Heart rate between 50-100 bpm, DBP between 40-100 mmHg and SBP between 90-170 mmHgextremities excluded,

9. Normal or non-clinically significant finding in ECG recording on a 10 min resting 12-lead ECG at the screening visit (left ventricular hypertrophy related withhypertension, will be allowed):

• HR [50-100 bpm],

• 110 ms ≤ interval between P and R waves (PR) < 220 ms,

• Interval between Q and S waves (QRS) < 120 ms,

• Fridericia corrected interval between Q and T waves (QTcF) ≤ 450 ms, 470 ms forfemale,

• No sign of any trouble of sinusal automatism,

• Or considered NCS by the Investigator,

7. Body Mass Index (BMI) between 18 and 35 kg/m² inclusive.

Additional inclusion criteria for matching controls

Matching controls will be required to satisfy all the following inclusion criteria to be included in the study:

1. Considered as healthy after a comprehensive clinical assessment (detailed medicalhistory and complete physical examination),

2. eGFR ≥ 90 mL/min/1.73 m²,

3. No proteinuria (i.e., no trace or positive dipstick results),

4. BMI between 18 and 35 kg/m2 inclusive and body weight,

5. Normal BP and heart rate (HR) at the screening visit after 5 min in supine position:

• 90 mmHg ≤ Systolic Blood Pressure (SBP) ≤ 145 mmHg, for elderly subjects (> 60years) an upper limit of 150 mmHg,

• 45 mmHg ≤ Diastolic Blood Pressure (DBP) ≤ 90 mmHg, for elderly subjects (> 60years) an upper limit of 95 mmHg,

• 50 bpm ≤ HR ≤ 100 bpm,

• Or value outside these limits but considered not clinically significant (NCS)by the Investigator,

6. Normal ECG recording on a 10 min resting 12-lead ECG at the screening visit:

• HR [50-100 bpm],

• 110 ≤ interval between P and R waves (PR) < 220 ms,

• Interval between Q and S waves (QRS) < 120 ms,

• Fridericia corrected interval between Q and T waves (QTcF) ≤ 450 ms, 470 ms forfemale,

• No sign of any trouble of sinusal automatism,

• Or considered NCS by the Investigator,

7. Laboratory parameters within the normal range or considered NCS by the Investigatorof the laboratory (hematological, blood chemistry tests, urinalysis). Individualvalues out of the normal range can be accepted if judged clinically non relevant bythe Investigator,

8. Normal dietary habits,

9. Matched to at least 1 renally impaired patient by ethnic group, sex, age (+/- 10years) and BMI (+/-20%).

Exclusion Criteria:

Non-inclusion criteria for all subjects

All the subjects/patients included in the study must not meet any of the following non-inclusion criteria:

1. Unsuitable veins for repeated venipuncture,

2. Positive Hepatitis B surface (HBsAg) antigen or positive Hepatitis C Virus (HCV), orpositive results for Human Immunodeficiency Virus (HIV)-1 or 2 tests,

3. History or presence of drug or alcohol abuse (alcohol consumption >40 grams/day),

4. Subject/Patient who, in the judgment of the Investigator, is likely to benon-compliant or uncooperative during the study, or unable to cooperate because of alanguage problem, poor mental development,

5. Subject/Patient who cannot be contacted in case of emergency,

6. History or presence of allergy or unusual reactions to some drugs or anesthetics orknown hypersensitivity to the investigation product or its excipients (includinglactose intolerance), test material or related compound,

7. Who receive a medication known to affect both cyochromes (CYP) CYP1A2, CYP3A4, andCYP2C19, such as rifampin, within 1 month prior to the first dose administration.Concomitant use of medications known to strongly affect either CYP1A2, CYP3A4, orCYP2C19, such as phenytoin, phenobarbital or carbamazepine, should be avoided within 1 month prior to the first dose administration.

8. Subject/Patient who is in the exclusion period of a previous study,

9. Administrative or legal supervision,

10. Blood donation (including in the frame of a clinical trial) within 2 months beforeadministration,

11. Subject/Patient who is pregnant, in labour or breastfeeding. Subject/Patient shouldnot be enrolled if she plans to become pregnant during the time of studyparticipation,

12. Excessive consumption of beverages with xanthine bases (> 4 cups or glasses / day),

13. Positive COVID 19 antigen test, or COVID-19 vaccination within 14 days of the firstdosing.

14. The consumption of grapefruit/grapefruits production, Sevilla oranges, or any poppyseeds, are not allowed from 7 days prior to the first study drug administration,

15. Evidence or history of clinically significant uncontrolled hematological, endocrine,pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic,metabolic, systemic, infectious, or allergic disease (including drughypersensitivity or allergies, but excluding untreated, asymptomatic, seasonalallergies at time of dosing). However, investigator will have the possibility tojudge whether a subject could be included with uncontrolled disease (e.g. in case ofnon-treated dyslipidemia),

16. General anesthesia within 3 months before administration,

17. Major surgery within 28 days prior to inclusion or major surgery planned during thenext 6 months,

18. Inability to abstain from intensive muscular effort,

19. Inability or difficulty swallowing whole capsules,

Additional non-inclusion criteria for renal impaired patients

Patients with renal impairment included in the study must not meet any of the following non-inclusion criteria:

1. History of renal transplant,

2. The patient has evidence of an unstable clinically important medical condition otherthan impaired renal function,

3. The patient has an acute exacerbation or unstable renal function, as indicated byworsening of clinical and/or laboratory signs of renal impairment, within the 4weeks before study drug administration,

4. Patients undergoing any method of dialysis or hemofiltration,

5. Disorders or surgery of the gastrointestinal tract which may interfere with drugabsorption or may otherwise influence the pharmacokinetics (PK) of theinvestigational medicinal product (IMP) (e.g., inflammatory bowel disease,resections of the small or large intestine, etc.),

6. History of febrile illness within 5 days prior to dosing,

7. Evidence of clinically significant liver disease or liver damage (e.g., hepatitis Bor C, autoimmune hepatitis, primary biliary cirrhosis, non-alcoholic fatty liverdisease, elevated aspartate aminotransferase (AST) or ALT that is consideredclinically significant by the Investigator, etc.),

8. Patient with a change in current treatments during the last month or receiving anydrug known to be potent CYP1A2, CYP3A4 and CYP2C19 inducers, such as rifampin. Additional non-inclusion criteria for matching controls Matching controls withnormal renal function included in the study must not meet any of the followingnoninclusion criteria:

9. Any history or presence of renal disease,

10. Frequent headaches (> twice a month) and / or migraines, recurrent nausea and / orvomiting,

11. Symptomatic hypotension whatever the decrease of blood pressure or asymptomaticpostural hypotension defined by a decrease in SBP (≥20 mmHg) or DBP (≥10 mmHg)within 2 min when changing from the supine to the standing position, Intake of anymedication (except paracetamol, hormonal contraceptives and hormone replacementtherapy for post-menopausal women), including over the counter (OTC) medications andherbal products, that could affect the outcome of the study is prohibited within 2weeks prior to the first drug administration or less than 5 times the t1/2 of thatdrug, whichever is the longer, or participant receiving any drug known to interferewith CYP enzymes within 1 month prior to the first dose administration.