Ascending-Dose Study of Noribogaine in Healthy Volunteers: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability
Ascending-Dose Study of Noribogaine in Healthy Volunteers: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability
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DOI：
10.1002/jcph.404
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发表时间：
2015-02-01
影响因子：
2.9
通讯作者：
Friedhoff, Lawrence
中科院分区：
文献类型：
--
作者：
Glue, Paul;Lockhart, Michelle;Friedhoff, Lawrence
Noribo是天然存在的精神活性物质ibo的活性代谢物，可能有助于抑制阿片类药物依赖者的戒断症状。这项I期研究的目的是评估诺瑞博韦的安全性、耐受性、药代动力学和药效学特征。在这项在36名健康无药物男性志愿者中进行的单次给药剂量递增、安慰剂对照、随机化、双盲、平行组研究中，4个队列（n = 9）接受了3、10、30或60 mg口服剂量或匹配安慰剂，并进行了长达216小时的强化安全性和药代动力学评估，沿着对μ阿片受体激动剂作用敏感的药效学评估。Noriboclavin被迅速吸收，在口服给药后2-3小时出现峰浓度，并且在3和60 mg之间显示浓度-时间曲线下面积（AUC）和C-max的剂量线性增加。药物缓慢消除，各剂量组的平均半衰期估计为28-49小时。表观分布容积较高（各剂量组的平均值为1417-3086 L）。在任何队列中均未发现安全性或耐受性问题。在瞳孔测量或冷加压试验中未观察到μ阿片激动剂药效学效应。在健康志愿者中，单次口服3-60 mg诺瑞波替尼是安全的，耐受性良好。
Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and C-max between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers.