Modeling sleep data for a new drug in development using Markov mixed-effects models
2011 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 28, no 10, 2610-2627 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2011. Vol. 28, no 10, 2610-2627 p.
Markov model, NONMEM, pharmacodynamics, polysomnography, population analysis, sleep, transition model, zolpidem
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-97672DOI: 10.1007/s11095-011-0490-xISI: 000294811700023OAI: oai:DiVA.org:uu-97672DiVA: diva2:172701