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

The purpose of this study is to determine whether the pharmacokinetics (PK) of stiripentol and of its relevant metabolites would be altered in subjects with renal impairment compared with normal controls in order to assess the need of dose adjustment in the renal impaired population. This study will include subjects with mild, moderate and severe renal impairment.

The pharmacokinetic studies conducted with stiripentol in humans evidenced that at steady state after multiple administration, up to 54.1%. of the stiripentol dose was excreted unchanged in hydrolyzed urine over the 24 h interval. Stiripentol is extensively metabolized by the liver; around 20 metabolites have been detected in urine, but the fraction of dose excreted as unchanged stiripentol is much less than one percent. At steady state, stiripentol and its metabolites in urine accounted collectively for 90% of the oral dose.

The risk of a clinically relevant increase in exposure in renal impairment is expected to be largest for drugs that are primarily renally eliminated, according to the European Medicines Agency (EMA) guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function and the draft Food and Drug Administration's (FDA) guidance for industry "Pharmacokinetics in Patients with Impaired Renal Function - Study Design, Data Analysis, and Impact on Dosing and Labeling". But since the literature shows that impaired renal function can alter some drug metabolism and transport pathways in the liver and gut a dedicated renal impairment study with a full pharmacokinetics (PK) design is recommended.

Therefore, the purpose of this study is to determine whether the pharmacokinetics (PK) of stiripentol and of its relevant metabolites would be altered in subjects with renal impairment compared with normal controls in order to assess the need of dose adjustment in the renal impaired population. This study will include subjects with mild, moderate and severe renal impairment.

Data from subjects with renal impairment will be compared to matched controls with normal renal function. Both groups should be similar with respect to sex, age, BMI and ethnicity. This approach is consistent with recommendations of the EMA guideline and FDA guidance for pharmacokinetics (PK) in patients with renal function as the control group in this study should be representative of the typical patient population for the drug under study, considering the patients' renal function and other factors known to affect the drug's pharmacokinetics (PK).

Plasma protein binding is often altered in patients with impaired renal function. Stiripentol is strongly bound (\>99%) to plasma proteins. Therefore, the EMA guideline and FDA guidance recommend the measurement of unbound drug concentrations. Therefore, the fraction of unbound stiripentol will be determined using two samples taken pre-dose and 3 h post-dose on Day 15 from each subject on-study.

Eligibility Criteria:
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 using highly effective contraception for the full duration of the study and for 1 month after the end of treatment,
3. Negative serum pregnancy test at screening and urinary pregnancy test at Day -1 (if applicable),
4. A negative antigen test for Coronavirus Disease 19 (COVID 19),
5. Normal hepatic function (AST \< 3xULN (Upper limit normal), ALT (Alanine aminotransferase); \<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 screening or longer,
2. Stable renal function (eGFR) as evidenced by ≤ 30% difference in two evaluations of Renal function (RF) on two separate occasions separated by at least 28 days with one measurement being the value at screening,
3. Renal impairment within the following ranges (using the Modification of Diet in Renal Disease-4 (MDRD4) equation) at screening:

   1. mild renal impairment with eGFR ≥ 60 to \< 90 mL/min/1.73 m²,
   2. moderate renal impairment with eGFR ≥ 30 to \< 60 mL/min/1.73 m²,
   3. severe renal impairment with eGFR \< 30 mL/min/1.73 m² and not on dialysis,
4. Supine blood pressure (BP) ≤ 180/104 mmHg,
5. Heart rate between 50-100 bpm, DBP between 40-100 mmHg and SBP between 90-170 mmHg extremities excluded,
6. 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 with hypertension, 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 for female,
   * 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 medical history 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 (\> 60 years) an upper limit of 150 mmHg,
   * 45 mmHg ≤ Diastolic Blood Pressure (DBP) ≤ 90 mmHg, for elderly subjects (\> 60 years) 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 for female,
   * 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 Investigator of the laboratory (hematological, blood chemistry tests, urinalysis). Individual values out of the normal range can be accepted if judged clinically non relevant by the Investigator,
8. Normal dietary habits,
9. Matched to at least 1 renally impaired patient by ethnic group, sex, age (+/- 10 years) 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), or positive 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 be non-compliant or uncooperative during the study, or unable to cooperate because of a language 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 or known hypersensitivity to the investigation product or its excipients (including lactose intolerance), test material or related compound,
7. Who receive a medication known to affect both cyochromes (CYP) CYP1A2, CYP3A4, and CYP2C19, such as rifampin, within 1 month prior to the first dose administration. Concomitant use of medications known to strongly affect either CYP1A2, CYP3A4, or CYP2C19, 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 before administration,
11. Subject/Patient who is pregnant, in labour or breastfeeding. Subject/Patient should not be enrolled if she plans to become pregnant during the time of study participation,
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 first dosing.
14. The consumption of grapefruit/grapefruits production, Sevilla oranges, or any poppy seeds, 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 drug hypersensitivity or allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). However, investigator will have the possibility to judge whether a subject could be included with uncontrolled disease (e.g. in case of non-treated dyslipidemia),
16. General anesthesia within 3 months before administration,
17. Major surgery within 28 days prior to inclusion or major surgery planned during the next 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 other than impaired renal function,
3. The patient has an acute exacerbation or unstable renal function, as indicated by worsening of clinical and/or laboratory signs of renal impairment, within the 4 weeks 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 drug absorption or may otherwise influence the pharmacokinetics (PK) of the investigational 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 B or C, autoimmune hepatitis, primary biliary cirrhosis, non-alcoholic fatty liver disease, elevated aspartate aminotransferase (AST) or ALT that is considered clinically significant by the Investigator, etc.),
8. Patient with a change in current treatments during the last month or receiving any drug known to be potent CYP1A2, CYP3A4 and CYP2C19 inducers, such as rifampin.

   Additional non-inclusion criteria for matching controls Matching controls with normal renal function included in the study must not meet any of the following noninclusion criteria:
9. Any history or presence of renal disease,
10. Frequent headaches (\> twice a month) and / or migraines, recurrent nausea and / or vomiting,
11. Symptomatic hypotension whatever the decrease of blood pressure or asymptomatic postural 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 any medication (except paracetamol, hormonal contraceptives and hormone replacement therapy for post-menopausal women), including over the counter (OTC) medications and herbal products, that could affect the outcome of the study is prohibited within 2 weeks prior to the first drug administration or less than 5 times the t1/2 of that drug, whichever is the longer, or participant receiving any drug known to interfere with CYP enzymes within 1 month prior to the first dose administration.