title: Modeling sleep data for a new drug in development using markov mixed-effects models.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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%.
  
  
  CONCLUSIONS
  The proposed accelerated model-building strategy resulted in a model well describing sleep patterns of insomnia patients with and without treatments.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. maria.kjellsson@farmbio.uu.se
authors.forename: Maria C
authors.initials: MC
authors.lastname: Kjellsson
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Brian
authors.initials: B
authors.lastname: Corrigan
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000085:Acetates / Q000627:therapeutic use*; D000328:Adult; D018592:Cross-Over Studies; D003517:Cyclopentanes / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D016014:Linear Models; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D017286:Polysomnography / Q000379:methods; D011725:Pyridines / Q000627:therapeutic use*; D012890:Sleep / Q000187:drug effects*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D012894:Sleep Stages / Q000187:drug effects*; D000077334:Zolpidem
chemical_list: C547571:(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid; D000085:Acetates; D003517:Cyclopentanes; D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem