M.J. van Esdonk (1,2), J. Stevens (2), P.H. van der Graaf (1), J. Burggraaf (1,2)
(1) Systems Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands. (2) Centre for Human Drug Research, Leiden, The Netherlands.
Objectives: A major disadvantage of standard deconvolution techniques is that the variable time is not taken forward in the analysis. Therefore, an integrated semi-population deconvolution method was developed to study the endogenous profile of growth hormone (GH) as a first step to better understand the pharmacodynamics of drugs targeting the secretion of GH.
Methods: This clinical trial consisted of 8 healthy and 16 obese female volunteers in which 24 hour GH profiles were measured at 10 minute sampling intervals. With deconvolution techniques, pulsatile data, such as GH profiles, can be analyzed and secretion parameters can be estimated (frequency of pulses, amplitude of pulses, etc.). AutoDecon [1], a fully automated deconvolution program, was used for the individual deconvolution analysis of the GH profiles. The deconvolution output was used in NONMEM 7.3 [2] for the development of a semi-population model in which individuals could retain their individual secretion profiles combined with the estimation of population parameters. Simulations of inhibiting and stimulating pharmacodynamic effects targeting the growth hormone secretion parameters were performed.
Results: The semi-population model was able to fit the data by defining each peak as a different occasion. Peaks were modelled as Gaussian shaped events being released in a 1 compartment model with a first order elimination. The population parameters in this model were the baseline secretion rate, secretion pulse width, secretion pulse amplitude and the growth hormone elimination rate constant. The pulse interval could not yet be implemented as a population parameter in this model structure.
Conclusions: Using the semi-population deconvolution method developed in this study, GH-profiles can be followed over time and the differences in growth hormone secretion between groups can be quantified. The simulations performed with the current model showed that it could be used to model scenarios that cannot not be identified by solely using traditional deconvolution analysis. The analysis method that has been developed in this study provides the opportunity to concurrently model the pharmacokinetics and pharmacodynamics of drugs that target the secretion of growth hormone.
References:
[1] MJ Johnson, L Pipes, PP Veldhuis, et al. AutoDecon: A Robust Numerical Method for the Quantification of Pulsatile Events. Methods Enzymol (2010). 454: 367–404.
[2] Beal SL, Sheiner LB, Boeckmann AJ, and Bauer RJ (eds) NONMEM 7.3.0 Users Guides. (1989–2013). ICON Development Solutions, Hanover, MD.
Reference: PAGE 25 () Abstr 5869 [www.page-meeting.org/?abstract=5869]
Poster: Methodology - New Modelling Approaches