DDMODEL00000125: ACTH_Cortisol_Circadian_Rhythm

  public model
Short description:
Model comprised of files: Simulated_ACTH_Cortisol.csv, Output_simulated_ACTH_Cortisol.lst, Command.txt, Output_real_ACTH_Cortisol.lst, ACTH_Cortisol.mod
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
Context of model development: Mechanistic Understanding;
Discrepancy between implemented model and original publication: None;
Long technical model description: The model contains a baseline production of ACTH plus surge functions representing the hormoal release during specific times of the day (morning and afternoon). Cortisol production was related to ACTH concentration in a nonlinear manner. Both ACTH and cortisol were modelled with one-compartment distribution and first-order elimination. Budesonide, given as inhalation, was modelled as inhibiting ACH production.;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: The aim was to create a model for the circadian rhythm in ACTH and cortisol. It was intended to increase the understanding of the dependence and asa tool fordevelopment of treatments interacting with the HPA axis.;
Modelling task in scope: estimation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: Endocrinology;
Annotations are correct.
This model is not certified.
  • Model owner: Mats Karlsson
  • Submitted: Dec 14, 2015 12:43:48 PM
  • Last Modified: Oct 21, 2016 4:10:14 PM
  • 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.