Lv Zhanhui, Zhang Zimo, Wang Lu, Zhou Sufeng, Sun Jianguo, Wang Xiuqin, Shao Feng
Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China.
Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Neuroendocrinology. 2025 Apr 25:1-14. doi: 10.1159/000546125.
This study investigates the circadian rhythm of melatonin in normal sleepers and delayed sleep-wake phase disorder (DSWPD) patients using quantitative pharmacology methods to better understand sleep disorders and their underlying mechanisms.
We developed an indirect effect model incorporating a surge function using data from 10 normal sleepers and 26 DSWPD patients. Model accuracy and stability were evaluated using diagnostic plots, visual predictive check, and bootstrap. Monte Carlo simulations (n = 1,000) quantitatively compared melatonin circadian rhythm characteristics between normal sleepers and DSWPD patients. Finally, Bayesian estimation utilizing external data from 3 normal sleepers and 3 DSWPD patients predicted melatonin concentration at different time points and the dim light melatonin onset (DLMO).
An indirect effect model incorporating a surge function effectively described the circadian rhythm of endogenous melatonin. The model estimates a population typical value (relative standard error %) of amplitude, 7.95 (15.47%); peak time, 23:59 (4.13%); peak width, 4.12 (5.78%); elimination rate constant, 1.23 h-1 (21.82%); baseline melatonin concentration, 3.21 pg/mL (23.27%). Monte Carlo simulation revealed that DSWPD patients exhibited approximately 7-h delay in DLMO, similar melatonin elimination rate constants, and a significantly lower melatonin production rate constants compared to normal sleepers. Bayesian estimation of the melatonin circadian characteristics and DLMO in DSWPD patients closely matched actual data, with model-estimated DLMO exhibiting an error margin within ±10%.
Compared to normal sleepers, DSWPD patients exhibited a reduced rate of melatonin production, similar rate of melatonin elimination, and delayed DLMO, highlighting notable circadian melatonin profile alterations. The final model employed Bayesian feedback to estimate melatonin circadian rhythm characteristics and DLMO in DSWPD patients using sparsely sampled data.
本研究采用定量药理学方法，调查正常睡眠者和睡眠-清醒时相延迟障碍（DSWPD）患者褪黑素的昼夜节律，以更好地了解睡眠障碍及其潜在机制。
我们利用10名正常睡眠者和26名DSWPD患者的数据，开发了一个包含激增函数的间接效应模型。使用诊断图、视觉预测检查和自助法评估模型的准确性和稳定性。蒙特卡洛模拟（n = 1000）定量比较了正常睡眠者和DSWPD患者之间褪黑素的昼夜节律特征。最后，利用来自3名正常睡眠者和3名DSWPD患者的外部数据进行贝叶斯估计，预测不同时间点的褪黑素浓度和暗光褪黑素起始时间（DLMO）。
包含激增函数的间接效应模型有效地描述了内源性褪黑素的昼夜节律。该模型估计的总体典型值（相对标准误差%）为：振幅7.95（15.47%）；峰值时间23:59（4.13%）；峰值宽度4.12（5.78%）；消除速率常数1.23 h-1（21.82%）；基线褪黑素浓度3.21 pg/mL（23.27%）。蒙特卡洛模拟显示，与正常睡眠者相比，DSWPD患者的DLMO延迟约7小时，褪黑素消除速率常数相似，而褪黑素生成速率常数显著更低。对DSWPD患者褪黑素昼夜节律特征和DLMO的贝叶斯估计与实际数据密切匹配，模型估计的DLMO误差幅度在±10%以内。
与正常睡眠者相比，DSWPD患者的褪黑素生成速率降低，褪黑素消除速率相似，且DLMO延迟，突出了昼夜褪黑素谱的显著改变。最终模型采用贝叶斯反馈，利用稀疏采样数据估计DSWPD患者的褪黑素昼夜节律特征和DLMO。
