Model selection and averaging of nonlinear mixed-effect models for robust phase III dose selection

Journal of Pharmacokinetics and Pharmacodynamics
Yasunori AokiAndrew C Hooker

Abstract

Population model-based (pharmacometric) approaches are widely used for the analyses of phase IIb clinical trial data to increase the accuracy of the dose selection for phase III clinical trials. On the other hand, if the analysis is based on one selected model, model selection bias can potentially spoil the accuracy of the dose selection process. In this paper, four methods that assume a number of pre-defined model structure candidates, for example a set of dose-response shape functions, and then combine or select those candidate models are introduced. The key hypothesis is that by combining both model structure uncertainty and model parameter uncertainty using these methodologies, we can make a more robust model based dose selection decision at the end of a phase IIb clinical trial. These methods are investigated using realistic simulation studies based on the study protocol of an actual phase IIb trial for an oral asthma drug candidate (AZD1981). Based on the simulation study, it is demonstrated that a bootstrap model selection method properly avoids model selection bias and in most cases increases the accuracy of the end of phase IIb decision. Thus, we recommend using this bootstrap model selection method when conducting pop...Continue Reading

References

Jul 27, 2001·Journal of Pharmacokinetics and Pharmacodynamics·U WählbyM O Karlsson
Jul 19, 2005·Computer Methods and Programs in Biomedicine·Lars LindbomNiclas Jonsson
Aug 18, 2005·Journal of Exposure Science & Environmental Epidemiology·Michael A Martin, Steven Roberts
May 25, 2007·Clinical Pharmacology and Therapeutics·R L LalondeR Miller
Jul 11, 2007·Journal of Pharmacokinetics and Pharmacodynamics·Yaning Wang
Nov 21, 2007·Journal of Biopharmaceutical Statistics·Björn BornkampFrank Shen
Dec 5, 2013·Statistics in Medicine·José PinheiroFrank Bretz
May 17, 2014·Nature Reviews. Drug Discovery·David CookMenelas N Pangalos
May 30, 2014·Clinical Trials : Journal of the Society for Clinical Trials·Dominique VerrierAnne-Catherine Solente

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Citations

May 28, 2019·Statistical Methods in Medical Research·Jérémy SeuratFrance Mentré
Jul 31, 2019·The AAPS Journal·Theodoros PapathanasiouAndrew C Hooker
Feb 16, 2020·The AAPS Journal·Antonio GonçalvesJérémie Guedj
Aug 2, 2020·Pharmaceutical Research·Gustaf J WellhagenMagnus Åstrand
Apr 25, 2018·The AAPS Journal·Theodoros PapathanasiouRune Viig Overgaard
Aug 21, 2019·Biometrika·K AlhornH Dette
Sep 17, 2020·Clinical Pharmacology and Therapeutics·Daniel Hill-McManusDyfrig A Hughes
Jul 29, 2021·CPT: Pharmacometrics & Systems Pharmacology·Yevgen RyeznikWeng Kee Wong

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Clinical Trials Mentioned

NCT01197794

Software Mentioned

GCC
ggplot2
PsN
R script
NONMEM
Linux
Perl
R
Scientific Linux
modelAverage

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