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DDMODEL00000125: ACTH Cortisol Circadian Rhythm Model

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Short description:
An model for the circadian rhythm of ACTH and cortisol in healthy volunteers following budesonide and placebo administration.
Original code
  • An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers.
  • Lönnebo A, Grahnén A, Karlsson MO
  • British journal of clinical pharmacology, 8/2007, Volume 64, Issue 2, pages: 125-132
  • Quintiles AB, Phase I Services, Uppsala and Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden. anna.lonnebo@quintiles.com
  • AIMS: Budesonide, a glucocorticosteroid, is used as a first-line treatment for asthma. The aim of the study was to develop a PK/PD model for the effect of budesonide on ACTH and cortisol. METHODS: The modelling data were generated by conducting a single-blind, randomized, placebo-controlled cross-over study. Ten healthy volunteers inhaled placebo (Placebo Turbohaler) and 1600 microg budesonide (Pulmicort Turbohaler), with a wash-out period of 7 days between treatments. Baseline concentrations of cortisol and ACTH were measured after placebo treatment and concentrations of cortisol, ACTH and budesonide were assessed after budesonide treatment. A one-compartment disposition model was used for budesonide disposition. Based on indirect response models, two types of models, distinguishing between production driven by a sum of cosine functions and production driven by surges, were used in parallel to describe the data. RESULTS: The surge-based approach was the most appropriate, based on goodness-of-fit, objective function values and number of parameters. The surge-based model that integrated both ACTH and cortisol data was chosen as the final model. The estimated half-lives of endogenous ACTH and cortisol were 9 and 113 min, respectively. The budesonide and ACTH concentrations producing 50% of the maximal response (IC(50) and A(50)) were 0.325 microg l(-1) and 4.96 pmol l(-1). CONCLUSIONS: The present PK/PD model of the effect of budesonide on ACTH and cortisol can serve as a tool for further understanding of the hypothalamic-pituitary-adrenal (HPA) axis and be useful in the development of drugs interacting with the axis.
Mats Karlsson
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  • Model owner: Mats Karlsson
  • Submitted: Dec 14, 2015 12:43:48 PM
  • Last Modified: Oct 21, 2016 4:10:14 PM
Revisions
  • Version: 20 public model Download this version
    • Submitted on: Oct 21, 2016 4:10:14 PM
    • Submitted by: Mats Karlsson
    • With comment: Edited model metadata online.
  • Version: 6 public model Download this version
    • Submitted on: Dec 14, 2015 12:43:48 PM
    • Submitted by: Mats Karlsson
    • With comment: Edited model metadata online.
 
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