Quantitative Pharmacology, EMD Serono, 45 Middlesex Turnpike, Billerica, MA, 01821, USA.
Biogen, Cambridge, MA, USA.
Clin Drug Investig. 2022 Oct;42(10):829-837. doi: 10.1007/s40261-022-01194-y. Epub 2022 Aug 31.
Vixotrigine is a voltage-dependent and use-dependent sodium channel blocker in development for the treatment of neuropathic pain. Metabolism of vixotrigine is primarily through glucuronidation, resulting in the major M13 metabolite. Two additional major metabolites formed are M14 and M16. This study was designed to evaluate the effects of a uridine diphosphate-glucuronosyltransferase inhibitor, valproic acid, on vixotrigine pharmacokinetics.
This open-label, fixed-sequence, phase I study enrolled 30 healthy volunteers who received a single dose of vixotrigine 150 mg on day 1 and day 16 following an 8-h fast. On days 8-22, volunteers received valproic acid 500 mg three times daily. A mixed-effects model was used to analyze the effect of valproic acid on the natural log-transformed pharmacokinetic parameters of vixotrigine and its metabolites including maximum concentration and area under the concentration-time curve from time zero to infinity.
Vixotrigine systemic exposure (area under the concentration-time curve from time zero to infinity) was increased by approximately 70% following the addition of valproic acid with a negligible effect on maximum concentration. Valproic acid administration also impacted vixotrigine metabolites: M13 exposure decreased by approximately 50% and M13 maximum concentration decreased by approximately 70%; increased exposure was noted for the M14 (approximately 100%) and M16 (approximately 70%) metabolites.
Valproic acid, a uridine diphosphate-glucuronosyltransferase inhibitor, significantly increased vixotrigine systemic exposure.
ClinicalTrials.gov Identifier: NCT03385525.
Vixotrigine 是一种电压依赖性和使用依赖性钠离子通道阻滞剂，正在开发用于治疗神经性疼痛。Vixotrigine 的代谢主要通过葡萄糖醛酸化，导致主要的 M13 代谢物。形成的另外两种主要代谢物是 M14 和 M16。本研究旨在评估尿苷二磷酸葡萄糖醛酸转移酶抑制剂丙戊酸对 vixotrigine 药代动力学的影响。
这项开放标签、固定序列、I 期研究纳入了 30 名健康志愿者，他们在禁食 8 小时后第 1 天和第 16 天接受了单剂量 150mg vixotrigine。在第 8-22 天，志愿者每天接受丙戊酸 500mg 三次。采用混合效应模型分析丙戊酸对 vixotrigine 及其代谢物（包括最大浓度和从零时到无穷大的浓度-时间曲线下面积）自然对数转化的药代动力学参数的影响。
加用丙戊酸后，vixotrigine 的全身暴露量（从零时到无穷大的浓度-时间曲线下面积）增加了约 70%，而最大浓度的影响可以忽略不计。丙戊酸的给药也影响了 vixotrigine 的代谢物：M13 的暴露量减少了约 50%，M13 的最大浓度减少了约 70%；M14（约 100%）和 M16（约 70%）代谢物的暴露量增加。
丙戊酸，一种尿苷二磷酸葡萄糖醛酸转移酶抑制剂，显著增加了 vixotrigine 的全身暴露量。
ClinicalTrials.gov 标识符：NCT03385525。
