Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Pharm Res. 2011 Oct;28(10):2610-27. doi: 10.1007/s11095-011-0490-x. Epub 2011 Jun 17.
To characterize the time-course of sleep in insomnia patients as well as placebo and concentration-effect relationships of two hypnotic compounds, PD 0200390 and zolpidem, using an accelerated model-building strategy based on mixed-effects Markov models.
Data were obtained in a phase II study with the drugs. Sleep stages were recorded during eight hours of sleep for two nights per treatment for the five treatments. First-order Markov models were developed for one transition at a time in a sequential manner; first a baseline model, followed by placebo and lastly the drug models. To accelerate the process, predefined models were selected based on a priori knowledge of sleep, including inter-subject and inter-occasion variability.
Baseline sleep was described using piece-wise linear models, depending on time of night and duration of sleep stage. Placebo affected light sleep stages; drugs also affected slow-wave sleep. Administering PD 0200390 30 min earlier than standard dosing was shown through simulations to reduce latency to persistent sleep by 40%.
The proposed accelerated model-building strategy resulted in a model well describing sleep patterns of insomnia patients with and without treatments.
利用基于混合效应马尔可夫模型的加速模型构建策略，描述失眠患者的睡眠时程以及两种催眠化合物 PD 0200390 和唑吡坦的浓度-效应关系。
该药物的 II 期研究中获得了数据。在每个治疗期的两个晚上，每个治疗期进行 8 小时的睡眠，记录睡眠阶段。以顺序方式一次为一个转变开发一阶马尔可夫模型；首先是基线模型，然后是安慰剂模型，最后是药物模型。为了加速这一过程，根据睡眠的先验知识，包括个体间和个体间变异性，选择了预定义的模型。
根据夜间时间和睡眠阶段持续时间，使用分段线性模型描述基线睡眠。安慰剂影响浅睡眠阶段；药物也影响慢波睡眠。通过模拟表明，将 PD 0200390 的给药时间提前 30 分钟，可将持续睡眠的潜伏期缩短 40%。
所提出的加速模型构建策略产生了一个很好的模型，描述了有和没有治疗的失眠患者的睡眠模式。
