Pharmaceutical Research

, 28:2610

Modeling Sleep Data for a New Drug in Development using Markov Mixed-Effects Models

  • Maria C. Kjellsson
  • Daniele Ouellet
  • Brian Corrigan
  • Mats O. Karlsson
Research Paper

DOI: 10.1007/s11095-011-0490-x

Cite this article as:
Kjellsson, M.C., Ouellet, D., Corrigan, B. et al. Pharm Res (2011) 28: 2610. doi:10.1007/s11095-011-0490-x



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.


Markov model NONMEM pharmacodynamics polysomnography population analysis sleep transition model zolpidem 

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Maria C. Kjellsson
    • 1
    • 5
  • Daniele Ouellet
    • 2
    • 3
  • Brian Corrigan
    • 4
  • Mats O. Karlsson
    • 1
  1. 1.Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden
  2. 2.Department of Clinical PharmacologyPfizer Global Research & DevelopmentAnn ArborUSA
  3. 3.Clinical Pharmacology/Modeling & Simulation, GlaxoSmithKlineDurhamUSA
  4. 4.Pfizer Global Research & Development, Clinical Research & Development, Pfizer Inc.GrotonUSA
  5. 5.Department of Pharmaceutical BiosciencesPharmacometrics Research GroupUppsalaSweden

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