Background

In recent randomized, placebo-controlled, phase III trials, highly purified cannabidiol demonstrated efficacy with an acceptable safety profile in patients with Lennox–Gastaut syndrome or Dravet syndrome. It is anticipated that antiepileptic drugs such as stiripentol and valproate will be administered concomitantly with cannabidiol.

Objectives

This trial evaluated the effect of cannabidiol on steady-state pharmacokinetics of stiripentol or valproate in patients with epilepsy, and the safety and tolerability of cannabidiol.

Methods

This phase II, two-arm, parallel-group, double-blind, randomized, placebo-controlled trial recruited male and female patients with epilepsy aged 16–55 years. Patients receiving a stable dose of stiripentol or valproate were randomized 4:1 to receive concomitant double-blind cannabidiol or placebo. Patients received plant-derived, highly purified cannabidiol medicine (Epidiolex^® in the USA; Epidyolex^® in the EU; 100 mg/mL oral solution) at a dose of 20 mg/kg/day from day 12 to 26, following a 10-day dose-escalation period. Blood samples for pharmacokinetic evaluations were collected on days 1 and 26 before stiripentol/valproate dosing and up to 12 h postdose. Treatment-emergent adverse events (AEs) were recorded.

Results

In total, 35 patients were recruited to the stiripentol arm (n = 14) or the valproate arm (n = 21). Both the safety and the pharmacokinetic populations of the stiripentol arm comprised 14 patients (2 placebo; 12 cannabidiol). The safety population of the valproate arm comprised 20 patients (4 placebo; 16 cannabidiol; one withdrew before receiving treatment); the pharmacokinetic population comprised 15 patients (3 placebo; 12 cannabidiol). Concomitant cannabidiol led to a small increase in stiripentol exposure (17% increase in maximum observed plasma concentration [C_max]; 30% increase in area under the concentration–time curve over the dosing interval [AUC_tau]). Concomitant cannabidiol also had little effect on valproate exposure (13% decrease in C_max; 17% decrease in AUC_tau) or its metabolite, 2-propyl-4-pentenoic acid (4-ene-VPA) (23% decrease in C_max; 30% decrease in AUC_tau). All changes in exposure are expressed as the dose-normalized geometric mean (CV%) day 26 to day 1 ratio. The most common AE was diarrhea; most AEs were mild. Two patients discontinued cannabidiol because of serious AEs (rash [n = 1] in the stiripentol arm; hypertransaminasemia [n = 1] in the valproate arm). A separate in vitro study investigated the bidirectional effect of cannabidiol, or its metabolite 7-carboxy-cannabidiol, on valproate plasma protein binding; no change in plasma protein binding was observed for either compound.

Conclusions

The clinical relevance of the increase in stiripentol exposure is unknown; patients receiving cannabidiol and stiripentol concomitantly should be monitored for adverse reactions as individual patient responses may vary. Coadministration of cannabidiol did not affect the pharmacokinetics of valproate or its metabolite, 4-ene-VPA, in adult patients with epilepsy. Safety results were consistent with the known safety profile of cannabidiol at a dose of 20 mg/kg/day.

Clinicaltrials.gov: NCT02607891.

中文翻译：

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一项 II 期随机试验，旨在探索在癫痫患者中与大麻二酚联合使用时司替戊醇或丙戊酸盐的药代动力学药物-药物相互作用的潜力。

背景

在最近的随机、安慰剂对照、III 期试验中，高度纯化的大麻二酚在 Lennox-Gastaut 综合征或 Dravet 综合征患者中证明了疗效和可接受的安全性。预计抗癫痫药如司替戊醇和丙戊酸盐将与大麻二酚同时给药。

目标

该试验评估了大麻二酚对癫痫患者司替戊醇或丙戊酸稳态药代动力学的影响，以及大麻二酚的安全性和耐受性。

方法

这项 II 期、双臂、平行组、双盲、随机、安慰剂对照试验招募了 16-55 岁的男性和女性癫痫患者。接受稳定剂量的司替戊醇或丙戊酸盐的患者以 4:1 的比例随机接受伴随的双盲大麻二酚或安慰剂。患者接受来自植物的，高度纯化的大麻二酚药物（Epidiolex ^®在USA; Epidyolex ^®在欧盟; 100mg / mL的口服溶液），剂量为12天20毫克/公斤/天至26，下面有10-日剂量递增期。在司替戊醇/丙戊酸盐给药前的第 1 天和第 26 天以及给药后最多 12 小时收集用于药代动力学评价的血液样本。记录了治疗中出现的不良事件 (AE)。

结果

总共有 35 名患者被招募到司替戊醇组 ( n = 14) 或丙戊酸组 ( n = 21)。司替戊醇组的安全性和药代动力学人群均包括 14 名患者（2 名安慰剂；12 名大麻二酚）。丙戊酸盐组的安全人群包括 20 名患者（4 名安慰剂；16 名大麻二酚；1 名在接受治疗前退出）；药代动力学人群包括 15 名患者（3 名安慰剂；12 名大麻二酚）。伴随大麻二酚导致司替戊醇曝光（一个小的增加观察到的最大血浆浓度增加17％[ C ^_最大值]; 30％的面积增加的浓度-时间曲线下在给药时间间隔[AUC _tau蛋白]）。伴随的大麻二酚对丙戊酸暴露（C _max降低 13% ；AUC _tau降低 17% ）或其代谢物 2-丙基-4-戊烯酸（4-烯-VPA）（C _max降低 23%）也几乎没有影响；AUC _tau降低 30% ）。暴露的所有变化均表示为第 26 天与第 1 天的剂量标准化几何平均值 (CV%)。最常见的 AE 是腹泻；大多数 AE 是轻微的。两名患者因严重 AE（司替戊醇组出现皮疹 [ n = 1]；高转氨血症 [ n= 1] 在丙戊酸臂中）。一项单独的体外研究调查了大麻二酚或其代谢物 7-羧基大麻二酚对丙戊酸血浆蛋白结合的双向影响；两种化合物的血浆蛋白结合均未观察到变化。

结论

司替戊醇暴露增加的临床相关性未知；同时接受大麻二酚和司替戊醇的患者应监测不良反应，因为个体患者的反应可能会有所不同。大麻二酚的共同给药不影响丙戊酸或其代谢物 4-烯-VPA 在成年癫痫患者中的药代动力学。安全性结果与 20 mg/kg/天剂量的大麻二酚的已知安全性一致。

Clinicaltrials.gov：NCT02607891。