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

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.