An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers.
OBJECTIVE
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.
Lönnebo
Anna
A
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
Grahnén
Anders
A
Karlsson
Mats O
MO
D000324:Adrenocorticotropic Hormone / Q000187:drug effects*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019819:Budesonide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D016037:Single-Blind Method; D016896:Treatment Outcome
D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D019819:Budesonide; D000324:Adrenocorticotropic Hormone