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

Kjellsson, Maria C.; Ouellet, Danièle; Corrigan, Brian; Karlsson, Mats O.

doi:10.1007/s11095-011-0490-x

Cited by 11 publications

(13 citation statements)

References 15 publications

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“…Sleep stages were determined according to previously published criteria, in which the subject was determined to be either awake, in stage 1, stage 2, stage 3, stage 4, or REM sleep for each epoch. 23 Stage 3 and stage 4 were collectively aggregated into a single stage called “slow-wave sleep.” 24 …”

Section: Methodsmentioning

confidence: 99%

Relationship Between Zolpidem Concentrations and Sleep Parameters in Pediatric Burn Patients

Stockmann

Gottschlich

Healy

et al. 2015

Journal of Burn Care & Research

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Zolpidem is a short-acting non-benzodiazepine hypnotic that is used to improve sleep architecture in patients with burn injuries. This study evaluated the relationship between zolpidem administration and sleep parameters in a cohort of children with severe burn injuries. Standard age-based zolpidem dosing practices were employed. Polysomnography data were recorded at 30-second intervals throughout the night. Serum concentrations of zolpidem were measured at 0, 1, 2, 4, 5, 6, and 8 hours after administration of the first dose. The relationship between zolpidem concentrations and sleep parameters was evaluated using Markov mixed-effects pharmacodynamic models. Ten children received two doses of zolpidem at 22:00 and 02:00 hours. The median total amount of sleep was 361.0 (interquartile range [IQR]: 299.0–418.5) minutes; approximately 65% of the normal reference value for an 8-hour period. Slow-wave and rapid eye movement (REM) sleep were also dramatically reduced (18–37% of normal). With two doses of zolpidem, stage 2 sleep was 99% of normal levels. Higher peak zolpidem concentrations were associated with increased stage 2 sleep (r2 = .54; P = .04). Despite this, a median of 120.0 (IQR: 99.5–143.5) transitions between nocturnal sleep stages were recorded, with a median of 55.5 (IQR: 36–75) night-time awakenings per patient. In pediatric burn patients, higher zolpidem serum concentrations were associated with restoration of stage 2 sleep to normal levels. Nonetheless, slow-wave and REM sleep were profoundly depressed with frequent transitions between sleep stages, suggesting that alternative hypnotic agents may be required to restore normal sleep architecture in severely burned children.

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Section: Methodsmentioning

confidence: 99%

Relationship Between Zolpidem Concentrations and Sleep Parameters in Pediatric Burn Patients

Stockmann

Gottschlich

Healy

et al. 2015

Journal of Burn Care & Research

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“…More expansive nonlinear mixed-effects models have previously been developed to estimate the transition probabilities to different sleep states [15][16][17][18][19] ; however, for this work, phase advanced sleep data were dichotomized (awake and asleep) to form the framework to investigate D-optimality for non-homogeneous (over time) discrete responses.…”

Section: Methodsmentioning

confidence: 99%

“…Estimation of the probability of transitioning to another state, or transition probability (TP), from each particular sleep stage to another was obtained through the implementation of a non-homogeneous Markovchain model, using a nonlinear mixed-effect approach, similar to that previously reported 16,17 . If Yi = (Yi1, Yi2… Yin) is the vector of observations for the i th subject, then the probability that Yit is equal to the stage m (m=0 or 1) at epoch= t, given that the preceding observation was k (k ≠ m), has the following general structure:…”

Section: Dichotomous Markov Mixed-effect Sleep Modelmentioning

confidence: 99%

“…As these models describe the individual likelihood of observing a discrete response, a higher order linearization (than the first order) is typically required due to the non-linear random effects 16,17 . Therefore, parameter estimation was performed using NONMEM 7.1.2 ® using the LAPLACE option 24 .…”

Section: Dichotomous Markov Mixed-effect Sleep Modelmentioning

confidence: 99%

“…The NLMEMs created to describe the sleep architecture for this type of polysomnography (PSG) data are partitioned into separate, smaller models (sub-models) based on the previous sleep state (Markov-chain) and estimate the transition probabilities to different sleep states [15][16][17][18][19] . To account for non-homogeneity over time, temporal dependence is implemented using piecewise linear functions.…”

Section: Introductionmentioning

confidence: 99%

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Optimal clinical trial design based on a dichotomous Markov-chain mixed-effect sleep model

Ernest

Nyberg

Karlsson

et al. 2014

J Pharmacokinet Pharmacodyn

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Optimal clinical trial design based on a dichotomous Markov-chain mixed-effect sleep model. Pharmacokinetics and Pharmacodynamics, 41(6) Journal of Abstract.Objectives: D-optimal designs for discrete-type responses have been derived using generalized linear mixed models, simulation based methods and analytical approximations for computing the Fisher information matrix (FIM) of non-linear mixed effect models with homogeneous probabilities over time. In this work, D-optimal designs using an analytical approximation of the FIM for a dichotomous, non-homogeneous, Markov-chain phase advanced sleep non-linear mixed effect model was investigated. Methods:The non-linear mixed effect model consisted of transition probabilities of dichotomous sleep data estimated as logistic functions using piecewise linear functions. Theoretical linear and nonlinear dose effects were added to the transition probabilities to modify the probability of being in either sleep stage. D-optimal designs were computed by determining an analytical approximation the FIM for each Markov component (one where the previous state was awake and another where the previous state was asleep). Each Markov component FIM was weighted either equally or by the average probability of response being awake or asleep over the night and summed to derive the total FIM (FIM total ). The reference designs were placebo, 0.1, 1-, 6-, 10-and 20-mg dosing for a 2-to 6-way crossover study in 6 dosing groups. Optimized design variables were dose and number of subjects in each dose group. The designs were validated using stochastic simulation/re-estimation (SSE).Results: Contrary to expectations, the predicted parameter uncertainty obtained via FIM total was larger than the uncertainty in parameter estimates computed by SSE. Nevertheless, the D-optimal designs decreased the uncertainty of parameter estimates relative to the reference designs. Additionally, the improvement for the D-optimal designs were more pronounced using SSE than predicted via FIM total . Conclusion: Through the use of an approximate analytic solution and weighting schemes, the FIM total for a non-homogeneous, dichotomous Markov-chain phase advanced sleep model was computed and provided more efficient trial designs and increased NLMEM parameter precision.

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N‐Heterocyclic Carbene Catalyzed [3+2] Cycloaddition of Enals with Masked Cinnamates for the Asymmetric One‐Pot Synthesis of Adipic Acid Derivatives

Chen

Sun

et al. 2017

Chemistry A European J

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A novel short entry to 3,4-disubstituted adipic acids has been developed by employing an asymmetric NHC-catalyzed [3+2] cycloaddition of enals with masked cinnammates in moderate to good yields and high stereoselectivities. The synthetic utility of the protocol was demonstrated by the basic conversion of the masked cyclopentanone intermediates to 3S,4S-disubstituted adipic acid precursors of pharmaceutically important gababutins.

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

Abstract: The proposed accelerated model-building strategy resulted in a model well describing sleep patterns of insomnia patients with and without treatments.

Cited by 11 publications

References 15 publications

Relationship Between Zolpidem Concentrations and Sleep Parameters in Pediatric Burn Patients

Relationship Between Zolpidem Concentrations and Sleep Parameters in Pediatric Burn Patients

Optimal clinical trial design based on a dichotomous Markov-chain mixed-effect sleep model

N‐Heterocyclic Carbene Catalyzed [3+2] Cycloaddition of Enals with Masked Cinnamates for the Asymmetric One‐Pot Synthesis of Adipic Acid Derivatives

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