An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers

Abstract

What is already known about this subject • The functionality of the HPA axis through cortisol production has been the subject for several investigations.• Modelling of cortisol production has been described by endogenous substance models utilizing a combination of indirect response functions and sum of cosine functions.• The effect of glucocorticoid drugs on cortisol production has been investigated using these models.What this study adds • Previous investigations (models) have not primarily considered the combined action of ACTH and cortisol.• Since ACTH drives cortisol production we adopted, for our modelling, the same approach as previous investigations but we distinguished between two types of models for the production of cortisol (driven by ACTH), one being the sum of cosine functions, the other being described by surges.• The presented surge-based model can serve as a tool for further understanding of the HPA axis and may also prove useful in the development of drugs interacting with the axis. AimsBudesonide, 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. MethodsThe modelling data were generated by conducting a single-blind, randomized, placebo-controlled cross-over study. Ten healthy volunteers inhaled placebo (Placebo Turbohaler) and 1600 mg 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. ResultsThe 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 (IC50 and A50) were 0.325 mg l -1 and 4.96 pmol l -1 . ConclusionsThe 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.

A population Pharmacokinetic Turnover and Surge‐Function Model for Describing Melatonin Biological Rhythm in Healthy Male Subjects

“…(3) contributes to the steepness at the onset of the melatonin surge. A value of 4 reportedly provided the best fit in surge models describing the effect of budesonide on ACTH and cortisol disposition in healthy volunteers,23 and for the release of luteinizing hormone into the bloodstream 15. In the current study, better precision of estimation and lower IIV was obtained using N = 8.…”

Approaches for modeling within subject variability in pharmacometric count data analysis: dynamic inter-occasion variability and stochastic differential equations

“…2) has previously been used to describe the time-course of hormonal surges (S) [8,9] estimating the time (T 0 ), amplitude (SA) and width (SW) of the surge. A modification (Eq.…”

Quantifying Pituitary-Adrenal Dynamics and Deconvolution of Concurrent Cortisol and Adrenocorticotropic Hormone Data by Compressed Sensing

“…These models describe cortisol synthesis in the adrenal glands based on the first-order kinetics of cortisol synthesis. Current mathematical models for concurrent ACTH and cortisol measurements include [21], [19], [23], [22], and [18]. Peters et al modeled ACTH and cortisol levels as a function of exogenous CRH [21].…”

“…They intravenously injected CRH to the participants, collected ACTH and cortisol levels until 4 hours after injection, and estimated the model parameters given the injected CRH [21]. Another data-driven model of concurrent ACTH and cortisol levels was proposed by Lonnebo et al where they assumed a surge-based nonlinear model with one morning surge and one afternoon surge [19]. Van Cauter proposed a method for recovering episodic hormone fluctuations [23], used it to analyze the 24-hour profile of concurrent ACTH and cortisol data and recovered the secretory events for each of the two hormone profiles [18], [22].…”