The power of modelling pulsatile profiles

Journal of Pharmacokinetics and Pharmacodynamics, vol. 48, pp. 439–444

Abstract

The quantitative description of individual observations in non-linear mixed effects models over time is complicated when the studied biomarker has a pulsatile release (e.g. insulin, growth hormone, luteinizing hormone). Unfortunately, standard non-linear mixed effects population pharmacodynamic models such as turnover and precursor response models (with or without a cosinor component) are unable to quantify these complex secretion profiles over time. In this study, the statistical power of standard statistical methodology such as 6 post-dose measurements or the area under the curve from 0 to 12 h post-dose on simulated dense concentration-time profiles of growth hormone was compared to a deconvolution-analysis-informed modelling approach in different simulated scenarios. The statistical power of the deconvolution-analysis-informed approach was determined with a Monte-Carlo Mapped Power analysis. Due to the high level of intra- and inter-individual variability in growth hormone concentrations over time, regardless of the simulated effect size, only the deconvolution-analysis informed approach reached a statistical power of more than 80% with a sample size of less than 200 subjects per cohort. Furthermore, the use of this deconvolution-analysis-informed modelling approach improved the description of the observations on an individual level and enabled the quantification of a drug effect to be used for subsequent clinical trial simulations.

Authors 2

1. Michiel Joost van Esdonk corresponding Aachen Centre for Human Drug Research (CHDR)

   Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research, Leiden, The Netherlands. mvesdonk@chdr.nl

   Centre for Human Drug Research, Leiden, The Netherlands

2. Jasper Stevens

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands