caa a22 4500 445313153 CHVBK 20180317142637.0 cr unu---uuuuu 170323e20111001xx s 000 0 eng 10.1007/s11095-011-0490-x doi (NATIONALLICENCE)springer-10.1007/s11095-011-0490-x Modeling Sleep Data for a New Drug in Development using Markov Mixed-Effects Models [Elektronische Daten] [Maria Kjellsson, Daniele Ouellet, Brian Corrigan, Mats Karlsson] ABSTRACT: Purpose: 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 30min earlier than standard dosing was shown through simulations to reduce latency to persistent sleep by 40%. Conclusion: The proposed accelerated model-building strategy resulted in a model well describing sleep patterns of insomnia patients with and without treatments. Springer Science+Business Media, LLC, 2011 Markov model nationallicence NONMEM nationallicence pharmacodynamics nationallicence polysomnography nationallicence population analysis nationallicence sleep nationallicence transition model nationallicence zolpidem nationallicence Kjellsson Maria Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden aut Ouellet Daniele Department of Clinical Pharmacology, Pfizer Global Research & Development, Ann Arbor, Michigan, USA aut Corrigan Brian Pfizer Global Research & Development, Clinical Research & Development, Pfizer Inc., Groton, Connecticut, USA aut Karlsson Mats Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2610-2627 0724-8741 28:10<2610 2011 28 11095 https://doi.org/10.1007/s11095-011-0490-x text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0490-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kjellsson Maria Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden aut NATIONALLICENCE 700 1- Ouellet Daniele Department of Clinical Pharmacology, Pfizer Global Research & Development, Ann Arbor, Michigan, USA aut NATIONALLICENCE 700 1- Corrigan Brian Pfizer Global Research & Development, Clinical Research & Development, Pfizer Inc., Groton, Connecticut, USA aut NATIONALLICENCE 700 1- Karlsson Mats Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2610-2627 0724-8741 28:10<2610 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer