Jogamoto Toshihiro, Yamamoto Yoshiaki, Fukuda Mitsumasa, Suzuki Yuka, Imai Katsumi, Takahashi Yukitoshi, Inoue Yushi, Ohtsuka Yoko
Department of Pediatrics, Ehime Prefectural Central Hospital, Japan; Department of Pediatrics, Ehime University Graduate School of Medicine, Japan.
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan.
Epilepsy Res. 2017 Feb;130:7-12. doi: 10.1016/j.eplepsyres.2016.12.014. Epub 2016 Dec 26.
Stiripentol (STP), valproate (VPA) and topiramate (TPM) are reported to have efficacy for Dravet syndrome. In this study, we sought to elucidate the mechanisms underlying the increased serum VPA concentrations following STP adjunctive therapy in patients with Dravet syndrome.
Twenty-eight patients with Dravet syndrome (age range, 1-35 years) undergoing combination therapy with VPA and STP were included in this study. We evaluated VPA and clobazam (CLB) serum concentrations before and after add-on STP. We also investigated potential factors impacting VPA metabolism during add-on STP therapy, including add-on TPM and CYP2C9 and CYP2C19 gene polymorphisms. The effect of STP on the metabolism of concomitantly administered CLB was also investigated.
Add-on STP was significantly associated with the serum concentration-to-dose (CD) ratio of VPA. Two patients, who were concomitantly treated with TPM, developed severe anorexia and thrombocytopenia because of marked increases in serum VPA concentrations. Further analysis revealed that the rate of increase in the VPA CD ratio was positively correlated with TPM dose. In patients not receiving TPM, STP enhanced the rate of increase in the VPA CD ratio to a significantly greater extent in CYP2C19 extensive metabolizers than in CYP2C19 poor metabolizers. Add-on STP was also associated with significant increases in CLB and N-desmethyl-CLB serum concentrations.
Our findings suggest that serum VPA concentrations should be carefully monitored during STP adjunctive therapy, particularly in patients receiving concomitant TPM therapy.
据报道，司替戊醇（STP）、丙戊酸盐（VPA）和托吡酯（TPM）对德雷维特综合征有效。在本研究中，我们试图阐明德雷维特综合征患者接受STP辅助治疗后血清VPA浓度升高的潜在机制。
本研究纳入了28例接受VPA和STP联合治疗的德雷维特综合征患者（年龄范围为1 - 35岁）。我们评估了加用STP前后的VPA和氯巴占（CLB）血清浓度。我们还研究了加用STP治疗期间影响VPA代谢的潜在因素，包括加用TPM以及CYP2C9和CYP2C19基因多态性。同时也研究了STP对同时服用的CLB代谢的影响。
加用STP与VPA的血清浓度 - 剂量（CD）比显著相关。两名同时接受TPM治疗的患者因血清VPA浓度显著升高而出现严重厌食和血小板减少。进一步分析显示，VPA CD比的升高率与TPM剂量呈正相关。在未接受TPM的患者中，与CYP2C19代谢缓慢者相比，STP使CYP2C19广泛代谢者的VPA CD比升高幅度显著更大。加用STP还与CLB和N - 去甲基 - CLB血清浓度的显著升高有关。
我们的研究结果表明，在STP辅助治疗期间应仔细监测血清VPA浓度，尤其是在接受TPM联合治疗的患者中。
