Abstract
Pharmacodynamic modeling of pulsatile endogenous compounds (e.g. growth hormone [GH]) is currently limited to the identification of a low number of pulses. Commonly used pharmacodynamic models are not able to capture the complexity of pulsatile secretion and therefore non-compartmental analyses are performed to extract summary statistics (mean, AUC, Cmax). The aim of this study was to develop a new quantification method that deals with highly variable pulsatile data by using a deconvolution-analysis-informed population pharmacodynamic modeling approach. Pulse frequency and pulse times were obtained by deconvolution analysis of 24 h GH profiles. The estimated pulse times then informed a non-linear mixed effects population pharmacodynamic model in NONMEM V7.3. The population parameter estimates were used to perform simulations that show agonistic and antagonistic drug effects on the secretion of GH. Additionally, a clinical trial simulation shows the application of this method in the quantification of a hypothetical drug effect that inhibits GH secretion. The GH profiles were modeled using a turnover compartment in which the baseline secretion, kout, pulse secretion width, amount at time point 0 and pulse amplitude were estimated as population parameters. Population parameters were estimated with low relative standard errors (ranging from 2 to 5%). Total body water (%) was identified as a covariate for pulse amplitude, baseline secretion and the pulse secretion width following a power relationship. Simulations visualized multiple gradients of a hypothetical drug that influenced the endogenous secretion of GH. The established model was able to fit and quantify the highly variable individual 24 h GH profiles over time. This pharmacodynamic model can be used to quantify drug effects that target other endogenous pulsatile compounds.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Pharmacology, University Medical Center Groningen, Groningen, The NetherlandsMany drugs exhibit wanted and/or unwanted effects on the secretion of endogenous pituitary hormones such as growth hormone (GH), prolactin or luteinizing hormone (LH)
Deconvolution analysis was previously performed on data from a clinical study where GH concentrations were sampled every 10 min over a 24 h period in normal weight, upper body obese (UBO) women with large visceral fat areas and lower body obese (LBO) women with small visceral fat areas, before and after weight loss [19]. This resulted in the identification of reduced GH secretion in UBO subjects and no significant difference in GH half-life or volume of distribution
The CV% on A_0 and Amplitude were high, which is in agreement with the observed high variability in the observed concentration at time point 0 and between the amplitude of pulses within an individual, respectively
Summary
Many drugs exhibit wanted and/or unwanted effects on the secretion of endogenous pituitary hormones such as growth hormone (GH), prolactin or luteinizing hormone (LH). When studying drug effects on the secretion of GH, a non-compartmental analysis on the plasma concentration–time profile is commonly performed. This results in mean and maximum plasma GH concentrations over a specified time interval or the area under the plasma GH concentration–time curve (AUC) to be used for comparison between groups [5,6,7]. By reducing the complex concentration–time profile of GH to
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