Division of Geriatric Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Pineal Res. 2012 May;52(4):437-45. doi: 10.1111/j.1600-079X.2011.00958.x. Epub 2012 Feb 21.
Melatonin is increasingly used for the treatment of sleep disorders. Surge-sustained formulations consisting of combined immediate release and controlled release dosing may mimic the endogenous melatonin physiologic profile. However, relatively little is known about the pharmacokinetic properties of low-dose (<0.5mg) and high-dose (>2mg) melatonin in a combined immediate release/controlled release dose, especially in older adults who may also exhibit altered melatonin disposition. To assess this, we conducted a randomized, double-blind, placebo-controlled study of low-dose (0.4mg) and high-dose (4.0mg) melatonin (25% immediate release+75% controlled release) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine whether melatonin pharmacokinetic properties differ between these two doses. The time to maximum level (1.3hrs versus 1.5hrs), elimination half-life (1.8hrs versus 2.1hrs), and apparent total clearance (379L/hr versus 478L/hr) did not differ significantly between the low- and high-dose arms, respectively. The maximum concentration was 405 ±93pg/mL for the low-dose arm and 3999±700pg/mL for the high-dose arm, both of which are substantially higher than physiologic melatonin levels for this age group. In addition, subjects in the high-dose arm maintained melatonin levels >50pg/mL for an average of 10hrs, which could result in elevated melatonin levels beyond the typical sleep period. Renal and liver function parameters remained stable after 6wks of treatment. The linear pharmacokinetic behavior of melatonin observed in the elderly can form the basis for future studies exploring a wider range of dosing scenarios to establish exposure-response relationships for melatonin-mediated sleep outcomes.
褪黑素越来越多地被用于治疗睡眠障碍。由即时释放和控制释放联合组成的持续释放制剂可能模拟内源性褪黑素的生理特征。然而，对于低剂量（<0.5mg）和高剂量（>2mg）褪黑素在联合即时释放/控制释放剂量中的药代动力学特性，人们知之甚少，特别是对于可能表现出改变的褪黑素处置的老年人。为了评估这一点，我们对 27 名有失眠抱怨和低内源性褪黑素水平的老年人进行了一项随机、双盲、安慰剂对照研究，以评估低剂量（0.4mg）和高剂量（4.0mg）褪黑素（25%即时释放+75%控制释放），以确定两种剂量之间褪黑素药代动力学特性是否存在差异。达到最大水平的时间（1.3 小时对 1.5 小时）、消除半衰期（1.8 小时对 2.1 小时）和表观总清除率（379L/hr 对 478L/hr）在低剂量和高剂量组之间无显著差异。低剂量组的最大浓度为 405±93pg/mL，高剂量组为 3999±700pg/mL，均远高于该年龄组的生理性褪黑素水平。此外，高剂量组的受试者平均保持褪黑素水平>50pg/mL 长达 10 小时，这可能导致褪黑素水平升高超过典型的睡眠时间。治疗 6 周后，肾功能和肝功能参数保持稳定。在老年人中观察到的褪黑素线性药代动力学行为可以为未来研究提供基础，探索更广泛的剂量方案，以建立褪黑素介导的睡眠结果的暴露-反应关系。
