Pharmacokinetic Variability of Sulthiame: The Impact of Age, Drug–Drug Interactions, and Biochemical Markers of Toxicity in Patients with Epilepsy

Abstract

Purpose: Sulthiame is an antiseizure medication increasingly used for epilepsy. The aim of this study was to investigate the pharmacokinetic variability of sulthiame in children and adults with epilepsy with respect to age, comedication, dose, serum concentration, and biochemical markers of toxicity in a clinical setting. Method: Retrospective quantitative data from the therapeutic drug monitoring (TDM) database at the Section for Clinical Pharmacology, the National Center for Epilepsy, Norway (2015–2021), were used. Results: TDM data from 326 patients (127 female/199 male) were included [mean age, 11.4 (range 2–44) years; mean weight, 41 (range 14–109) kg]. Interindividual pharmacokinetic variability in the concentration/(dose/body weight) (C/(D/kg)) ratio was 16-fold; intraindividual variability was up to 8-fold (coefficient of variation = 10%–78%). Young children (younger than 6 years) had a significantly lower C/(D/kg) ratio than older age groups (P < 0.05). Various comedications did not significantly affect the C/(D/kg) ratio, possibly owing to the small sample size. However, CYP2C19-mediated inhibition by sulthiame was indicated because patients using clobazam and sulthiame (n = 28) had a 3.5-fold higher N-desmethylclobazam C/(D/kg) ratio than those using neutral comedication (n = 45; P < 0.001). Patients with pH values below the adjusted normal range (7.32–7.42; n = 15) had a 33% higher sulthiame concentration than those with normal pH values (n = 22; P < 0.05). Blood gas measurements, especially pH, may serve as markers of toxicity and can be used in combination with clinical data when toxicity is suspected. Conclusions: This study revealed the extensive intraindividual and interindividual pharmacokinetic variability of sulthiame, with age as a contributing factor. Sulthiame has clinically relevant interactions with clobazam. The use of TDM and pH as a biochemical marker may contribute to individualized and safe sulthiame treatment.