HTL0009936是一种选择性M1毒蕈碱受体激动剂,可用于阿尔茨海默病的认知功能障碍。安全,在认知功能低于平均水平(BAF)的老年受试者中,研究了在稳态下连续静脉输注HTL0009936的耐受性,药代动力学和探索性药效学效应.
A部分是一项针对健康老年人的四治疗开放标签序贯研究,研究10-83mgHTL0009936(IV)和24mgHTL0009936单次口服剂量。B部分是随机的五个治疗,双盲,安慰剂和毒扁豆碱对照交叉研究与IVHTL0009936老年受试者与BAF。使用神经认知和电生理测试进行药效学评估。
HTL0009936的药代动力学显示暴露的剂量成比例增加,平均半衰期为2.4小时。HTL0009936对短暂的剂量相关不良事件(AE)耐受性良好。在B部分的最高剂量下,平均收缩压有7.12mmHg(95%CI[3.99-10.24])和舒张压有5.32mmHg(95%CI[3.18-7.47])的小幅升高。有暗示性,但没有确定的,积极或消极的药效学作用。使用HTL0009936和使用毒扁豆碱的适应性追踪对P300观察到统计学上的显着影响。
HTL0009936显示出良好表征的药代动力学,单剂量在健康的老年受试者中是安全的,并且通常具有良好的耐受性。由于毒扁豆碱耐受性问题和受试者负担,改变了研究设计,并在次优药物暴露时进行了一些药效学评估(神经认知).因此,尽管对P300的影响暗示了中心靶标参与,但对HTL0009936的药效学效果没有明确的结论。
HTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer\'s disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF).
Part A was a four-treatment open label sequential
study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over
study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests.
Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine.
HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the
study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.