Isabelle Pouliquen, Lutz Harnisch
GlaxoSmithKline, CPDM, CPK, M&S, Greenford, London, UK
Cortisol levels in the plasma follow a circadian variation with its peak in the early morning and a trough in the late afternoon. A well-known negative feedback loop exists in which ACTH partly via CRH release controls cortisol levels.
Any interaction with the natural cycle of cortisol production, release, and metabolism is prone to cause adverse side effects. The therapeutic administration of cortisol derivatives in the treatment of asthma, COPD or other inflammatory diseases will make a certain amount of the drug systemically available even if administered non-orally, i.e. per inhalation.
Especially in the chronic treatment of inflammatory diseases it is highly desirable to keep systemic exposure of drugs low and also to optimise the time course of the administration to cause the least impact on the cortisol life cycle.
Aim of the present work is to develop a population PK/PD model for cortisol, its daily variation and its dependency on exogenous administration of cortisol derivatives.
Based on literature information a structural model for the cortisol population data was developed using the work of Chakraborty1, Rohatagi2, and Meibohm3 who used single subject data and different models to describe the circadian variation. The main purpose of the present work was to integrate the different models and to develop a population PK/PD model allowing extensive clinical trial simulations for new compounds and various dosing regimens.
A positive constrained 3-harmonic Fourier series input function was best in describing the cortisol baseline characteristics. The steroid induced suppression of the endogenous cortisol release was introduced via an Emax link function to the systemic exposure of the exogenous administered drug.
In order to derive the population PK/PD model data from various previous sources were used, i.e. cortisol response data after placebo and drug administration and also drug exposure data.
The potential clinical target was defined as the minimal cortisol suppression during a 24hour daily cycle. To achieve an optimal separation of desirable and adverse reactions simulations can be performed based on the derived model using any given dose, exposure, administration site, or potency of a given compound.
References:
[1] A Chakraborty, W Krzyzanski, W Jusko. Mathematical modeling of circadian cortisol concentrations using indirect response models: comparison of several methods. JPB, 1999[27], 23-43
[2] S Rohatagi, A Bey, A Mackie, H Derendorf. Mathematical modeling of cortisol circadian rhythm and cortisol suppression. EJPharmSci, 1996[4], 341-350
[3] B Meibohm, G Hochhaus, H Moellmann, J Barth, M Wagner, M Krieg, R Stoeckmann, H Derendorf. A pharmacokinetic/pharmacodynamic approach to predict the cumulative cortisol suppression of inhaled corticosteroids. JPB, 1999[27], 127-147
Reference: PAGE 13 (2004) Abstr 516 [www.page-meeting.org/?abstract=516]
Poster: poster