Department of Pharmacy, Oslo Metropolitan University, Oslo, Norway.
Department of Pharmacology, Oslo University Hospital, Oslo, Norway.
Ther Drug Monit. 2024 Oct 1;46(5):664-671. doi: 10.1097/FTD.0000000000001219. Epub 2024 May 15.
Rufinamide and stiripentol, orphan drugs used in Lennox-Gastaut and Dravet syndromes, respectively, are antiseizure medications (ASMs), often administered to children; however, pharmacokinetic studies are lacking. The authors compared the pharmacokinetic variability of these drugs with respect to the dose, serum concentrations, comedication, age, and duration of treatment.
Children and adolescents (<18 years) whose serum concentrations were measured were retrospectively identified from the therapeutic drug monitoring (TDM) databases at 2 national epilepsy centers in Norway and Denmark (2012-2021).
Data from 165 patients (56% boys/44% girls) treated with rufinamide and 52 patients (50% boys/50% girls) treated with stiripentol were included. For rufinamide, the median age was 10 (range 2-17) years, dose 23 (3-73) mg/d, and serum concentration 34 (3-227) µmol/L [8.1 mg/L (0.71-54.0 mg/L)]. For stiripentol, the median age was 8.5 (range 1-17) years, dose 37 (18-76) mg/d, and serum concentration 33 (4-113) µmol/L [7.7 mg/L (0.93-26.3 mg/L)]. The concomitant use of 1-9 other ASMs during the data collection was noted. Pharmacokinetic variability, calculated as the concentration/(dose/kg) ratio, ranged from 0.26 to 11.31 (µmol/L)/(mg/kg) for rufinamide and 0.17-1.52 (µmol/L)/(mg/kg) for stiripentol. The intraindividual coefficients of variation ranged widely, from 5% to 110% for rufinamide and 11%-117% for stiripentol. The treatment period was at least 5 years in 50% of patients. No statistically significant effects of age, sex, or ASM comedication were observed, possibly due to the small sample size and heterogeneous groups with variable seizure situations, comorbidities, and changes in comedication and physiology.
This study demonstrates considerable pharmacokinetic variability in and between patients for both drugs and similar use in terms of age, burden of comedication and retention rates. TDM may be useful in the clinical setting to monitor and optimize treatment in this vulnerable patient group.
鲁非酰胺和司替戊醇分别是用于 Lennox-Gastaut 综合征和 Dravet 综合征的孤儿药，属于抗癫痫药物（ASM），常被用于儿童；但目前缺乏药代动力学研究。作者比较了这两种药物的药代动力学变异性，包括剂量、血清浓度、合并用药、年龄和治疗持续时间。
从挪威和丹麦的 2 个国家癫痫中心的治疗药物监测（TDM）数据库中回顾性地确定了血清浓度被测量的 165 名接受鲁非酰胺治疗的儿童和青少年（56%男孩/44%女孩）和 52 名接受司替戊醇治疗的患者（50%男孩/50%女孩）。鲁非酰胺组的中位年龄为 10 岁（范围 2-17 岁），剂量为 23 毫克/天（范围 3-73 毫克/天），血清浓度为 34 微摩尔/升（范围 3-227 微摩尔/升）[8.1 毫克/升（0.71-54.0 毫克/升）]。司替戊醇组的中位年龄为 8.5 岁（范围 1-17 岁），剂量为 37 毫克/天（范围 18-76 毫克/天），血清浓度为 33 微摩尔/升（范围 4-113 微摩尔/升）[7.7 毫克/升（0.93-26.3 毫克/升）]。在数据收集期间，注意到同时使用了 1-9 种其他 ASM。药代动力学变异性，以浓度/剂量（kg）比表示，鲁非酰胺为 0.26-11.31（微摩尔/升）/（毫克/千克），司替戊醇为 0.17-1.52（微摩尔/升）/（毫克/千克）。个体内变异系数范围很广，鲁非酰胺为 5%-110%，司替戊醇为 11%-117%。50%的患者治疗时间至少为 5 年。未观察到年龄、性别或 ASM 合并用药的统计学显著影响，这可能是由于样本量小且分组不均，伴有不同的癫痫发作情况、合并症以及合并用药和生理情况的变化。
本研究表明，两种药物的患者间和患者内均存在相当大的药代动力学变异性，且在年龄、合并用药负担和保留率方面具有相似性。治疗药物监测可能有助于临床监测，优化这一脆弱患者群体的治疗。
