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Home / Equine Research Bank / J Pharmacokinet Pharmacodyn / Modelling of oscillatory cortisol response in horses using a...
Journal of pharmacokinetics and pharmacodynamics2019; 46(1); 75-87; doi: 10.1007/s10928-018-09617-0

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

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.
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Publication Date: 2019-01-23 PubMed ID: 30673914PubMed Central: PMC6394511DOI: 10.1007/s10928-018-09617-0Google Scholar: Lookup
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  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research article investigates how well the dexamethasone suppression test (DST) protocol works to diagnose pituitary pars intermedia dysfunction (PPID) in horses by modelling the interplay between cortisol and dexamethasone. The study uses simulation models to identify potential improvements in the DST protocol to avoid false positive results.

Understanding the Biological Basis

  • PPID is a disease that affects the regulation of cortisol, a steroid hormone relevant to immune function in horses and other species that typically shows a circadian rhythm (or daily cycle).
  • Dexamethasone, a glucocorticoid, is used to suppress cortisol in horses and the DST tests the functional integrity of this suppression mechanism.
  • If the cortisol suppression response to dexamethasone is abnormal, it may indicate the presence of PPID.

Problem with Existing Protocols

  • The study acknowledges that existing DST protocols have been performing poorly in previous experimental studies. They often wrongly suggest the presence of PPID in healthy horses, which are termed false positive results.

Modelling Approach

  • To address the above issues, the researchers used a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to study the oscillatory (fluctuating or rhythmic) cortisol response and its interaction with dexamethasone.
  • Using a Bayesian population approach, the model can quantify uncertainty and make predictions for a larger population of horses beyond just those sampled in this study.

Analysis of DST Protocols

  • The researchers scrutinized two existing DST protocols using the simulations generated by the model.
  • Particular attention was paid to the capability of these protocols to avoid false positive results.

Impact of Dose Selection and Sampling Time

  • The research found that both the selection of the dexamethasone dose and the timing of sample collection could greatly affect the number of false positive results.

Improvement Suggestions

  • The study offers suggestions for potential pitfalls in current test protocols and proposes directions for improving DST protocols.
  • The methodology presented can be easily extended to other clinical test protocols, indicating its broader impact and usage.

Cite This Article

APA
Held F, Ekstrand C, Cvijovic M, Gabrielsson J, Jirstrand M. (2019). Modelling of oscillatory cortisol response in horses using a Bayesian population approach for evaluation of dexamethasone suppression test protocols. J Pharmacokinet Pharmacodyn, 46(1), 75-87. https://doi.org/10.1007/s10928-018-09617-0

Publication

Journal of pharmacokinetics and pharmacodynamics
ISSN: 1573-8744
NlmUniqueID: 101096520
Country: United States
Language: English
Volume: 46
Issue: 1
Pages: 75-87

Researcher Affiliations

Held, Felix
  • Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden. felix.held@chalmers.se.
  • Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden. felix.held@chalmers.se.
Ekstrand, Carl
  • Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Cvijovic, Marija
  • Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden.
Gabrielsson, Johan
  • Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Jirstrand, Mats
  • Fraunhofer-Chalmers Centre, Chalmers Science Park, Gothenburg, Sweden.

MeSH Terms

  • Animals
  • Bayes Theorem
  • Circadian Rhythm / drug effects
  • Dexamethasone / pharmacology
  • Glucocorticoids / pharmacology
  • Horses
  • Hydrocortisone / metabolism
  • Pituitary Diseases / drug therapy
  • Pituitary Diseases / metabolism

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Citations

This article has been cited 2 times.
  1. Tou K, Cawley A, Bowen C, Sornalingam K, Fu S. Measurements of hydrocortisone and cortisone for longitudinal profiling of equine plasma by liquid chromatography-tandem mass spectrometry. Drug Test Anal 2022 May;14(5):943-952.
    doi: 10.1002/dta.3244pubmed: 35195373google scholar: lookup
  2. Ekstrand C, Pettersson H, Gehring R, Hedeland M, Adolfsson S, Lilliehöök I. Prednisolone in Dogs-Plasma Exposure and White Blood Cell Response. Front Vet Sci 2021;8:666219.
    doi: 10.3389/fvets.2021.666219pubmed: 34179161google scholar: lookup
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