Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity
Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity
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DOI：
10.1111/j.1528-1157.1997.tb01486.x
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发表时间：
1997-09-01
期刊：
影响因子：
5.6
通讯作者：
Lee, DA
中科院分区：
文献类型：
--
作者：
Monaghan, EP;Navalta, LA;Lee, DA
目的：研究抗癫痫药物加那洛酮的安全性、耐受性和药代动力学。Ganaxolone属于一种新型的神经活性类固醇，称为epalons，它可以特异性调节中枢神经系统（CNS）中的γ -氨基丁酸a型（GABA）受体。在化学上与黄体酮有关，但没有任何激素活性，对动物有有效的抗癫痫、抗焦虑、镇静和催眠作用。方法：96名健康的男性和女性志愿者接受了各种配方、剂量和给药方案的加那索龙。系统地描述了加那洛酮的药代动力学，并记录了与药物使用相关的不良事件。结果：单次给药（≤1500mg）和多次给药（≤300mg，每日10天）加那洛酮耐受性良好。稳态血浆浓度（谷）发生在与给药相似的7天后，多次给药研究中的平均稳态血浆浓度（C-max）在32 ng/ml （50 mg剂量）和376 ng/ml （500 mg剂量）之间。未观察到与该药有关的严重或危及生命的不良事件。报告的大多数不良事件为轻度（82%）至中度（14%），仅限于头痛、头晕、嗜睡、胃肠道紊乱和不适。结论：口服50 ~ 1500mg剂量的加那洛酮单用或与药用级赋形剂配制后，可迅速从胃肠道吸收。药代动力学分析显示，在预期治疗剂量范围内，随着剂量的增加，曲线下面积（AUC）和C-max值呈线性比例增加。临床试验的安全性和耐受性无显著差异。
Purpose: Studies were conducted to establish the safety, tolerability, and pharmacokinetics of the antiepileptic drug (AED) ganaxolone. Ganaxolone belongs to a novel class of neuroactive steroids called epalons, which specifically modulate the gamma-aminobutyric acid type A (GABA(A)) receptor in the central nervous system (CNS). Chemically related to progesterone but devoid of any hormonal activity, the epalons have potent antiepileptic, anxiolytic, sedative, and hypnotic activities in animals.Methods: Ninety-six healthy male and female volunteers received ganaxolone in a variety of formulations, doses, and dosing regimens. The pharmacokinetics of ganaxolone were systematically characterized, and adverse events associated with drug use were documented.Results: Ganaxolone was well tolerated after single doses (less than or equal to 1,500 mg) and after multiple doses (less than or equal to 300 mg b.i.d. for 10 days). Steady-state plasma levels (trough) occurred after similar to 7 days of dosing, with mean steady-state plasma concentrations (C-max) in multiple dose studies of between 32 ng/ml (50-mg doses) and 376 ng/ml (500-mg doses). No serious or life-threatening adverse events attributed to the drug were observed. The majority of adverse events reported were mild (82%) to moderate (14%) and were limited to headache, dizziness, somnolence, gastrointestinal disturbances, and malaise.Conclusions: Ganaxolone alone or formulated with pharmaceutical-grade excipients is rapidly absorbed from the gastrointestinal tract after oral administration in doses ranging from 50 to 1,500 mg. Pharmacokinetic analysis revealed a linear and proportional increase in the area under the curve (AUC) and C-max values with increasing dose within the expected therapeutic dose range. Safety and tolerability in the clinical program were unremarkable.