Introduction

HTL0018318 is a selective muscarinic M₁ receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer’s disease. Clinically, HTL0018318 would likely be used alone or in conjunction with cholinesterase inhibitors (e.g. donepezil).

Objective

We investigated the safety, tolerability, and pharmacokinetics of HTL0018318 given alone and in combination with donepezil.

Methods

This was a randomized, double-blind, placebo-controlled trial in 42 (to deliver 36 with combination treatment) healthy elderly subjects investigating the effects of oral HTL0018318 15 and 25 mg given alone and combined with donepezil 10 mg at steady state on adverse events (AEs), vital signs, saliva production, sleep quality, pulmonary function, subjective feelings, and pharmacokinetics.

Results

AEs were reported by lower percentages of subjects after HTL0018318 alone than after donepezil alone. There was no increase in the percentage of subjects reporting AEs after co-administration than after donepezil alone. Supine systolic blood pressure was 1.6 mmHg (95% confidence interval [CI] −3.1 to −0.1) lower after HTL0018318 alone than after combination treatment. This was comparable with results from placebo alone: 1.7 mmHg (95% CI −3.2 to 0.2) lower than with combination treatment. Supine pulse rate was 3.3 bpm (95% CI 1.5–5.1) higher after HTL0018318 alone than with co-administration. HTL0018318 and donepezil did not meaningfully affect each other’s pharmacokinetics.

Conclusion

HTL0018318 was well tolerated when given alone and in combination with donepezil. HTL0018318 and donepezil do not demonstrate pharmacokinetic or pharmacodynamic interactions, indicating that HTL0018318 can be safely administered in combination with donepezil.

Clinical trial registration

Netherlands Trial register identifier NL5915, registered on 28 October 2016.

中文翻译：

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HTL0018318，一种新型 M1 受体激动剂，在稳态时与多奈哌齐联合给药的安全性和药代动力学：一项在健康老年受试者中的随机试验

介绍

HTL0018318 是一种选择性毒蕈碱 M ₁受体部分激动剂，正在开发中，用于对症治疗痴呆症，包括阿尔茨海默病。临床上，HTL0018318 可能单独使用或与胆碱酯酶抑制剂（例如多奈哌齐）联合使用。

客观的

我们研究了 HTL0018318 单独给药和与多奈哌齐联合给药的安全性、耐受性和药代动力学。

方法

这是一项随机、双盲、安慰剂对照试验，涉及 42 名（36 名联合治疗）健康老年受试者，研究单独口服 HTL0018318 15 和 25 毫克以及与稳态多奈哌齐 10 毫克联合对不良事件的影响(AE)、生命体征、唾液分泌、睡眠质量、肺功能、主观感觉和药代动力学。

结果

与单独使用多奈哌齐相比，单独使用 HTL0018318 后受试者报告的 AE 百分比较低。与单独服用多奈哌齐相比，共同给药后报告 AE 的受试者百分比没有增加。单用 HTL0018318 后仰卧收缩压比联合治疗后低 1.6 mmHg（95% 置信区间 [CI] -3.1 至 -0.1）。这与单独使用安慰剂的结果相当：比联合治疗低 1.7 mmHg（95% CI -3.2 至 0.2）。单用 HTL0018318 后仰卧脉搏率比联合用药高 3.3 bpm (95% CI 1.5–5.1)。HTL0018318 和多奈哌齐对彼此的药代动力学没有显着影响。

结论

HTL0018318 单独给药和与多奈哌齐联合给药时耐受性良好。HTL0018318 和多奈哌齐未表现出药代动力学或药效学相互作用，表明 HTL0018318 可以安全地与多奈哌齐联合给药。

临床试验注册

荷兰 试用注册标识符 NL5915，于 2016 年 10 月 28 日注册。