Department of Pediatric Neurology, Centre de Reference des Epilepsies Rares, Inserm U663, Hopital Necker Enfants Malades, APHP, Paris Descartes University, Paris, France.
Eur J Paediatr Neurol. 2012 Sep;16 Suppl 1:S13-7. doi: 10.1016/j.ejpn.2012.04.009. Epub 2012 Jun 12.
The efficacy of stiripentol (STP) in Dravet Syndrome (DS) was discovered first in an exploratory study in pediatric pharmacoresistant epilepsies. This efficacy signal, used as a proof of concept, led to - two independent multicenter randomized, double-blind, placebo-controlled trials in DS patients: STICLO-France and STICLO-Italy. In adjunction to valproate and clobazam, STP demonstrated marked efficacy and these trials became the basis for the registration of STP as an orphan drug for DS. Although STP had previously shown antiepileptic activity, since it inhibits cytochromes P450, the increased plasma levels of clobazam (CLB), norclobazam (NCLB), and NCLB/CLB ratio reported in STICLO studies brought into question the activity of STP per se. Recent pharmacological studies demonstrated that (i) STP is a direct allosteric modulator of the GABA receptors at a site distinct from benzodiazepines; (ii) STP and CLB/NCLB act independently at GABA(A) receptors; (iii) their combination increases the maximum response beyond that of either drug alone. All these effects are independent of considerations of changes in metabolism. Some responders in STICLO studies failed to display any increase of plasmatic concentrations of NCLB/CLB ratio as STP could not inhibit CYP2C19 because of its inhibition by progabide or due to an inactivating CYP polymorphism. The responder rate proved to be in the same range whether the NCLB/CLB ratio increased or not. These analyses confirmed that the effects of STP cannot result from a simple pharmacokinetic interaction. We propose that the success of STP should serve as a model for AED development in rare pediatric epileptic syndromes.
司替戊醇（STP）在德拉维综合征（DS）中的疗效最初是在儿科抗药性癫痫的探索性研究中发现的。这一疗效信号作为概念验证，导致了两项独立的多中心、随机、双盲、安慰剂对照试验在 DS 患者中进行：STICLO-France 和 STICLO-Italy。除了丙戊酸和氯巴占外，STP 显示出明显的疗效，这些试验成为 STP 作为 DS 孤儿药注册的基础。尽管 STP 先前已经显示出抗癫痫活性，但由于它抑制细胞色素 P450，STICLO 研究报告的氯巴占（CLB）、去甲氯巴占（NCLB）和 NCLB/CLB 比值的血浆水平升高，引发了对 STP 本身活性的质疑。最近的药理学研究表明：（i）STP 是 GABA 受体的直接变构调节剂，作用部位不同于苯二氮䓬类药物；（ii）STP 和 CLB/NCLB 独立作用于 GABA(A)受体；（iii）它们的组合增加了最大反应，超过了单独使用任何一种药物的反应。所有这些作用都与代谢变化无关。STICLO 研究中的一些应答者未能显示任何 NCLB/CLB 比值的血浆浓度增加，因为 STP 不能抑制 CYP2C19，因为它被丙戊酰胺抑制或由于 CYP 多态性失活。无论 NCLB/CLB 比值是否增加，应答者的比率都证明在相同的范围内。这些分析证实，STP 的作用不能归因于简单的药代动力学相互作用。我们提出，STP 的成功应该为罕见儿科癫痫综合征的 AED 开发提供一个模型。
