2010 - Berlin - Germany

PAGE 2010: Methodology- Model evaluation
Roberto Bizzotto

PK-PD modeling of Wake after Sleep Onset time-course

Bizzotto R (1), Zamuner S (2)

(1) Dept. of Information Engineering, University of Padova, Italy; (2) Clinical Pharmacology/Modeling&Simulation, GlaxoSmithKline, Verona, Italy.

Objectives: Wake after Sleep Onset (WASO) quantifies the night time spent awake after falling in a persistent sleep state and is considered one of the key sleep parameters to characterize the effect of a hypnotic drug. SB-649868 is a potent orexin antagonist with demonstrated ability of decreasing such clinical endpoint. A pharmacokinetic-pharmacodynamic (PK-PD) model using total WASO (i.e., WASO on the whole night) has recently been developed [1]. The aim of this work is to model SB-649868 effect on WASO time course (i.e., WASO by hour), and to compare WASO time-course vs. total WASO model outcomes.

Methods: Pharmacokinetic (PK) and pharmacodynamic (PD) data were collected in a polysomnography randomized, double-blind, placebo-controlled, cross-over study. 52 subjects spent two nights in each arm of the study. Plasma concentrations data were analyzed using a non-linear mixed-effect approach as implemented in NONMEM VI. Modeled PK profiles were then used to characterize WASO time-course, i.e. the time spent awake in each hour of the night after falling asleep persistently at least once. The final PK-PD model was used for predicting both WASO time-course and total WASO after treatment with different doses using an improved formulation.

Results: A PK-PD model was developed assuming that each contribution to total WASO (observed at 1-hour intervals) was described by its own typical parameter, in the logit scale. The individual deviation from the typical logit value of a specific interval was assumed to belong to a normal distribution and correlated to the deviations of the same subject in the other intervals. A first night effect and a treatment effect were found to be statistically significant. A Weibull model was found to best describe the concentration-related effect. Statistically relevant differences among different night intervals were detected in certain parameters of the Weibull model. Visual predictive check (VPC) showed good performance of the model for both WASO time-course and total WASO. When comparing the new PK-PD model to the previous one on total WASO [1], similar outcomes were obtained on the VPC level, but residual unexplained variability was reduced. In the simulations using the improved formulation the residual variability dropped from 30% to 10% with the new approach.

Conclusions: A new PK-PD model has been developed for accurately assessing both the time-course and the total WASO, after treatment with SB-649868. Residual variability was lower considering the time-course model. This model is more appropriate to thoroughly characterize the potential effect of changes in doses and formulation.

References:

[1] Zamuner S, Nucci G, Bettica P, Gerrard P, Squassante L, Gomeni R. Clinical Pharmacokinetic-Pharmacodynamic Model of SB-649868 in Insomnia, Preclinical and Clinical Correlates. In SLEEP, Volume 32, Abstract Supplement, 2009. Abstract nr 0853




Reference: PAGE 19 (2010) Abstr 1933 [www.page-meeting.org/?abstract=1933]
Poster: Methodology- Model evaluation
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