Department of Clinical Research, NHO, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders.
Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, University of Shizuoka; and.
Ther Drug Monit. 2020 Apr;42(2):302-308. doi: 10.1097/FTD.0000000000000676.
Stiripentol is a strong inhibitor of CYP2C19 and CYP3A4. This study compared the effect of stiripentol on the pharmacokinetics of clobazam and N-desmethyl-clobazam (NCLB; an active metabolite of clobazam) between different CYP2C19 phenotypes. We also evaluated the clinical impact of CYP2C19 phenotypes in Japanese patients with Dravet syndrome receiving a combination of valproic acid, clobazam, and stiripentol.
We retrospectively reviewed 241 blood samples from 64 patients (aged 1-40 years) and calculated the concentration/dose (CD) ratio [serum level (ng/mL) divided by dose (mg/kg)] for clobazam and NCLB. Based on their CYP2C19 genotypes, patients were classified as extensive metabolizers (EM group: CYP2C19*1/*1, *1/*2, or *1/3) or poor metabolizers (PM group: CYP2C192/*2, *3/*3, or *2/*3). We also reviewed the clinical records of 56 patients who commenced stiripentol therapy and calculated the retention rate for stiripentol therapy over an observation period of 208 weeks.
Concomitant administration of stiripentol led to a marked increase in the CD ratio of clobazam (1.8-fold in the EM group and 1.5-fold in the PM group). In addition, stiripentol increased the CD ratio of NCLB by 6.6-fold in the EM group, but decreased it by 0.7-fold in the PM group. The estimated retention rate with stiripentol therapy was higher, and the duration of retention was longer in the EM group than in the PM group (1378 versus 933 days, P < 0.001). In patients with the PM phenotype, the adjusted hazard ratio for ceasing stiripentol therapy was 6.7 (95% confidence interval: 1.8-24.7, P < 0.005).
The effect of stiripentol on the pharmacokinetics of NCLB was significantly different between patients with the EM and PM phenotypes, which could influence the clinical response of Japanese patients with Dravet syndrome receiving the combination of valproic acid, clobazam, and stiripentol.
斯替戊醇是 CYP2C19 和 CYP3A4 的强抑制剂。本研究比较了斯替戊醇对不同 CYP2C19 表型的氯巴占及其 N-去甲基氯巴占（氯巴占的活性代谢物，NCLB）药代动力学的影响。我们还评估了 CYP2C19 表型对日本 Dravet 综合征患者接受丙戊酸、氯巴占和斯替戊醇联合治疗的临床影响。
我们回顾性分析了 64 例（年龄 1-40 岁）患者的 241 份血样，并计算了氯巴占和 NCLB 的浓度/剂量（CD）比值[血清水平（ng/mL）除以剂量（mg/kg）]。根据 CYP2C19 基因型，患者分为广泛代谢者（EM 组：CYP2C19*1/*1、*1/2 或1/3）或弱代谢者（PM 组：CYP2C192/*2、*3/3 或2/*3）。我们还回顾了 56 例开始斯替戊醇治疗的患者的临床记录，并计算了观察 208 周期间斯替戊醇治疗的保留率。
同时给予斯替戊醇可使氯巴占的 CD 比值显著升高（EM 组 1.8 倍，PM 组 1.5 倍）。此外，斯替戊醇使 EM 组的 NCLB 的 CD 比值增加了 6.6 倍，但在 PM 组中降低了 0.7 倍。EM 组的估计保留率更高，保留时间也更长（1378 天 vs 933 天，P<0.001）。在 PM 表型患者中，停止斯替戊醇治疗的调整后危险比为 6.7（95%置信区间：1.8-24.7，P<0.005）。
斯替戊醇对 EM 和 PM 表型患者 NCLB 药代动力学的影响有显著差异，这可能影响接受丙戊酸、氯巴占和斯替戊醇联合治疗的日本 Dravet 综合征患者的临床反应。
