Modelling of oscillatory cortisol response in horses using a Bayesian population approach for evaluation of dexamethasone suppression test protocols

Felix Held,Carl Ekstrand,Johan Gabrielsson,Marija Cvijovic,Mats Jirstrand

doi:10.1007/s10928-018-09617-0

Abstract

Cortisol is a steroid hormone relevant to immune function in horses and other species and shows a circadian rhythm. The glucocorticoid dexamethasone suppresses cortisol in horses. Pituitary pars intermedia dysfunction (PPID) is a disease in which the cortisol suppression mechanism through dexamethasone is challenged. Overnight dexamethasone suppression test (DST) protocols are used to test the functioning of this mechanism and to establish a diagnosis for PPID. However, existing DST protocols have been recognized to perform poorly in previous experimental studies, often indicating presence of PPID in healthy horses. This study uses a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to analyse the oscillatory cortisol response and its interaction with dexamethasone. Two existing DST protocols were then scrutinized using model simulations with particular focus on their ability to avoid false positive outcomes. Using a Bayesian population approach allowed for quantification of uncertainty and enabled predictions for a broader population of horses than the underlying sample. Dose selection and sampling time point were both determined to have large influence on the number of false positives. Advice on pitfalls in test protocols and directions for possible improvement of DST protocols were given. The presented methodology is also easily extended to other clinical test protocols.

Highlights

IntroductionDexamethasone and other glucocorticoids are commonly used in equine medicine for the treatment of diseases and clinical testing, e.g., the dexamethasone suppression test
Dexamethasone and other glucocorticoids are commonly used in equine medicine for the treatment of diseases and clinical testing, e.g., the dexamethasone suppression testElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.(DST) [1,2,3]
Within and between subject variability in the dexamethasone time courses were low, which suggests that exposure of dexamethasone does not confound the cortisol response

Summary

Introduction

Dexamethasone and other glucocorticoids are commonly used in equine medicine for the treatment of diseases and clinical testing, e.g., the dexamethasone suppression test. Dexamethasone suppresses the cortisol response [4, 5]. The mechanism is challenged in horses affected by pituitary pars intermedia dysfunction (PPID) [6]. PPID is an age-related degenerative disease leading to a loss of dopaminergic neurons affecting the pars intermedia of the pituitary gland [7]. Similarities of PPID to Parkinson’s disease in humans have been found [8]. The most prevalent clinical signs of PPID in horses are hair coat abnormalities, laminitis and muscle atrophy [9]. The prevalence of PPID in horses aged more than 15 years is 21% [10]

Methods

Results

Discussion

Conclusion