Heger Katrine, Kjeldstadli Kari, Ring Nelly, Aaberg Kari Modalsli, Kjeldsen Signe Flood, Burns Margrete Larsen, Johannessen Svein I, Johannessen Landmark Cecilie
Department of Pharmacy, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway.
Section for Clinical Pharmacology, Department of Pharmacology, Oslo University Hospital, Oslo, Norway.
Ther Drug Monit. 2024 Apr 1;46(2):237-245. doi: 10.1097/FTD.0000000000001146. Epub 2023 Dec 27.
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.
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.
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.
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.
舒噻美是一种越来越多地用于治疗癫痫的抗癫痫药物。本研究的目的是在临床环境中，研究舒噻美在儿童和成人癫痫患者中的药代动力学变异性，涉及年龄、合并用药、剂量、血清浓度和毒性生化标志物。
使用挪威国家癫痫中心临床药理学部门治疗药物监测（TDM）数据库（2015 - 2021年）的回顾性定量数据。
纳入了326例患者（127例女性/199例男性）的数据[平均年龄11.4（范围2 - 44）岁；平均体重41（范围14 - 109）kg]。浓度/（剂量/体重）（C/（D/kg））比值的个体间药代动力学变异性为16倍；个体内变异性高达8倍（变异系数 = 10% - 78%）。幼儿（6岁以下）的C/（D/kg）比值显著低于年龄较大的组（P < 0.05）。各种合并用药对C/（D/kg）比值没有显著影响，可能是由于样本量较小。然而，提示舒噻美存在CYP2C19介导的抑制作用，因为使用氯巴占和舒噻美的患者（n = 28）的N - 去甲基氯巴占C/（D/kg）比值比使用中性合并用药的患者（n = 45；P < 0.001）高3.5倍。pH值低于调整后正常范围（7.32 - 7.42）的患者（n = 15）的舒噻美浓度比pH值正常的患者（n = 22；P < 0.05）高33%。血气测量，尤其是pH值，可作为毒性标志物，在怀疑有中毒情况时可与临床数据结合使用。
本研究揭示了舒噻美广泛的个体内和个体间药代动力学变异性，年龄是一个影响因素。舒噻美与氯巴占存在临床相关的相互作用。使用TDM和pH值作为生化标志物可能有助于舒噻美的个体化和安全治疗。
