Pharmacological Laboratory, Society for Epilepsy Research, Bielefeld, Germany.
Ther Drug Monit. 2012 Aug;34(4):390-7. doi: 10.1097/FTD.0b013e31825dc4a6.
Stiripentol (STP) was approved as an orphan drug in 2007 in Europe as adjunctive therapy with valproic acid (VPA) and clobazam (CLB) for Dravet syndrome. Dravet syndrome is a highly pharmacoresistant form of epilepsy, which starts in early childhood. Data about STP pharmacokinetics and interactions are still limited and in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily STP dose per body weight (milligrams per kilogram), VPA, CLB, and enzyme-inducing antiepileptic drugs on STP concentration-to-dose ratio (CDR), STP clearance, and STP trough concentrations.
Retrospectively, 220 STP serum concentrations in 75 patients from 3 German Epilepsy Centers were analyzed. Analysis of variance, regression analysis, and generalized estimating equations were used for statistical analysis.
Our findings confirm the nonlinear STP pharmacokinetics. At steady state, STP CDR increased with daily STP doses. Compared with patients older than 12 years, STP concentrations were decreased by 39.6% in children aged 6-12 years (P < 0.001) and by 57.5% in children younger than 6 years (P < 0.001). Phenobarbital and phenytoin decreased STP concentrations by 63.2%. This effect was highly significant (P < 0.001), despite the small number of patients (n = 7) treated with phenobarbital or phenytoin. VPA had no significant effect on STP serum concentrations, whereas STP serum concentrations were moderately but significantly increased by CLB (24.6%, P = 0.011).
Therapeutic drug monitoring of STP seems to be useful because of the wide variation of STP CDR, the nonlinear concentration-to-dose relationship, age-dependent pharmacokinetics, and drug-drug interactions.
司替戊醇（STP）于 2007 年在欧洲被批准为孤儿药，作为添加疗法与丙戊酸（VPA）和氯巴占（CLB）联合用于德拉维氏综合征。德拉维氏综合征是一种高度耐药的癫痫形式，始于儿童早期。关于 STP 药代动力学和相互作用的数据仍然有限，部分数据不一致。我们研究的目的是分析年龄、性别、每日 STP 剂量与体重的比值（毫克/千克）、VPA、CLB 和酶诱导抗癫痫药物对 STP 浓度-剂量比（CDR）、STP 清除率和 STP 谷浓度的影响。
回顾性分析了来自德国 3 个癫痫中心的 75 例患者的 220 次 STP 血清浓度。采用方差分析、回归分析和广义估计方程进行统计学分析。
我们的研究结果证实了 STP 的非线性药代动力学。在稳态时，STP CDR 随每日 STP 剂量增加而增加。与年龄大于 12 岁的患者相比，6-12 岁儿童的 STP 浓度降低了 39.6%（P < 0.001），6 岁以下儿童的 STP 浓度降低了 57.5%（P < 0.001）。苯巴比妥和苯妥英降低了 STP 浓度，降低幅度分别为 63.2%（P < 0.001）。尽管接受苯巴比妥或苯妥英治疗的患者数量较少（n = 7），但这种影响具有高度显著性。VPA 对 STP 血清浓度无显著影响，而 CLB 则使 STP 血清浓度适度但显著升高（24.6%，P = 0.011）。
由于 STP CDR 的广泛变化、非线性浓度-剂量关系、年龄相关的药代动力学和药物相互作用，STP 的治疗药物监测似乎是有用的。
