Safety, Tolerability, and Pharmacokinetics of Adrenomedullin in Healthy Males: A Randomized, Double-Blind, Phase 1 Clinical Trial
Safety, Tolerability, and Pharmacokinetics of Adrenomedullin in Healthy Males: A Randomized, Double-Blind, Phase 1 Clinical Trial
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DOI：
10.2147/dddt.s225220
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发表时间：
2020-01-01
影响因子：
4.8
通讯作者：
Kitamura, Kazuo
中科院分区：
文献类型：
--
作者：
Kita, Toshihiro;Kaji, Yoshikazu;Kitamura, Kazuo
背景：肾上腺髓质素（AM）是一种内源性血管舒张肽，具有免疫调节作用，是消化道粘膜再生的加速剂。AM在炎症性肠病和溃疡性结肠炎的啮齿动物模型中显示出有益的作用。本研究旨在通过一期临床试验评估AM在健康男性中的药效学特性和安全性。方法：本研究为一期随机、双盲、单中心研究，研究对象为20 ~ 65岁的健康男性。受试者接受安慰剂、3 ng/kg/min AM、9 ng/kg/min AM或15 ng/kg/min AM连续12小时静脉输注。其他受试者接受安慰剂或15 ng/kg/min AM治疗，每天8小时，持续7天。评估不良事件（ae）、生命体征、体格检查、实验室检查、心电图（ECG）和药代动力学。结果：单剂量试验的24名受试者全部完成了研究。在多次给药试验的12名受试者中，AM组有1人因头痛退出。没有严重的ae报告。所有受试者的血流动力学参数均保持良好。单剂量试验观察到轻微的心电图异常。血浆AM浓度呈剂量依赖性逐渐升高，并在给药结束时达到C-max。血浆AM终止后迅速恢复到基线浓度，T-1/2小于60分钟。解释：这是在健康男性中评估AM安全性的第一个一期试验。我们的研究结果证明了AM在后续二期试验中的安全性和耐受性。
Background: Adrenomedullin (AM), an endogenous vasodilative peptide, has immunomodulative effects and acts as an accelerator of mucosal regeneration in the digestive tract. AM has shown beneficial effects in rodent models of inflammatory bowel disease and patients with ulcerative colitis. The present study aimed to evaluate the pharmacodynamic properties and safety of AM in healthy male adults in a phase 1 clinical trial.Methods: This phase 1, randomized, double-blind, single-center study was conducted on healthy males aged 20-65 years. Subjects received either a placebo, 3 ng/kg/min AM, 9 ng/kg/min AM, or 15 ng/kg/min AM via continuous 12-h intravenous infusion. Other subjects received either placebo or 15 ng/kg/min AM for 8 h per day for 7 days. Adverse events (AEs), vital signs, physical examinations, laboratory tests, electrocardiograms (ECG), and pharmacokinetics were assessed.Findings: All 24 subjects in the single-dose test completed the study. Of the 12 subjects in multiple dosing test, one from the AM group withdrew owing to a headache. No serious AEs were reported. Hemodynamic parameters were well maintained in all subjects. Slight ECG abnormalities were observed in the single-dose test. The plasma concentration of AM progressively increased in a dose-dependent manner and reached C-max at the end of administration. Plasma AM rapidly returned to baseline concentrations after termination, with a T-1/2 of under 60 min.Interpretation: This is the first phase 1 trial in healthy men evaluating the safety of AM. Our results demonstrate the safety and tolerability of AM for subsequent Phase 2 trials.