N,N-二甲基色胺在人体内的药代动力学,European Journal of Drug Metabolism and Pharmacokinetics

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N,N-二甲基色胺在人体内的药代动力学
European Journal of Drug Metabolism and Pharmacokinetics ( IF 1.9 ) Pub Date : 2023-04-22 , DOI: 10.1007/s13318-023-00822-y
Meghan Good ₁ , Zelah Joel ₁ , Tiffanie Benway ₁ , Carol Routledge ₁ , Chris Timmermann ₂ , David Erritzoe ₂ , Richard Weaver ₃ , Graham Allen ₄ , Charlotte Hughes ₅ , Helen Topping ₅ , Amy Bowman ₆ , Ellen James ₁

Affiliation

背景和目的

N , N-二甲基色胺 (DMT) 是一种迷幻化合物，正在开发用于治疗重度抑郁症 (MDD)。本研究评估了健康受试者中 DMT 的临床前和临床药代动力学和代谢。

方法

通过一系列体外实验确定了 DMT 的理化性质，并使用肝细胞和线粒体组分中的单胺氧化酶 (MAO) 和细胞色素 P450 (CYP) 抑制剂评估其代谢特征。临床药代动力学结果来自 I/IIa 期随机、双盲、安慰剂对照、平行组剂量递增试验 (NCT04673383) 的 I 期部分。健康成人通过两相静脉 (IV) 输注接受单次递增剂量的 DMT 富马酸盐 (SPL026)。剂量方案是根据药代动力学模型和预测计算的，并根据安全性和耐受性进展到每个后续剂量水平。

结果

通过抑制 MAO-A、CYP2D6 和较小程度的 CYP2C19，可以降低 DMT 的体外清除率。亲脂性和血浆蛋白结合测定结果较低，表明高比例的DMT可用于分布和代谢，与非常快速的临床药代动力学一致。24 名健康受试者接受了剂量递增的 DMT，输注时间为 10 分钟，剂量范围为 9–21.5 mg（DMT 游离碱）。所有剂量的 DMT 均被迅速清除：平均消除半衰期为 9-12 分钟。所有剂量均安全且耐受性良好，并且 DMT 血浆峰值浓度与体重指数 (BMI) 或体重之间没有关系。

结论

这是第一项详细确定人体缓慢静脉输注后 DMT 完整药代动力学特征的研究，证实快速达到血浆峰值浓度，然后快速清除。这些发现提供了支持开发治疗 MDD 的新型 DMT 输注方案的证据。

临床试验注册

在 ClinicalTrials.gov 上注册 (NCT04673383)。

"点击查看英文标题和摘要"

Pharmacokinetics of N,N-dimethyltryptamine in Humans

Background and Objective

N,N-dimethyltryptamine (DMT) is a psychedelic compound under development for the treatment of major depressive disorder (MDD). This study evaluated the preclinical and clinical pharmacokinetics and metabolism of DMT in healthy subjects.

Methods

The physiochemical properties of DMT were determined using a series of in vitro experiments and its metabolic profile was assessed using monoamine oxidase (MAO) and cytochrome P450 (CYP) inhibitors in hepatocyte and mitochondrial fractions. Clinical pharmacokinetics results are from the phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial (NCT04673383). Healthy adults received single escalating doses of DMT fumarate (SPL026) via a two-phase intravenous (IV) infusion. Dosing regimens were calculated based on pharmacokinetic modelling and predictions with progression to each subsequent dose level contingent upon safety and tolerability.

Results

In vitro clearance of DMT was reduced through the inhibition of MAO-A, CYP2D6 and to a lesser extent CYP2C19. Determination of lipophilicity and plasma protein binding was low, indicating that a high proportion of DMT is available for distribution and metabolism, consistent with the very rapid clinical pharmacokinetics. Twenty-four healthy subjects received escalating doses of DMT administered as a 10-min infusion over the dose range of 9–21.5 mg (DMT freebase). DMT was rapidly cleared for all doses: mean elimination half-life was 9–12 min. All doses were safe and well tolerated and there was no relationship between peak DMT plasma concentrations and body mass index (BMI) or weight.

Conclusion

This is the first study to determine, in detail, the full pharmacokinetics profile of DMT following a slow IV infusion in humans, confirming rapid attainment of peak plasma concentrations followed by rapid clearance. These findings provide evidence which supports the development of novel DMT infusion regimens for the treatment of MDD.