Related Experiment Video
Updated: Aug 10, 2026

Expression of Exogenous Cytokine in Patient-derived Xenografts via Injection with a Cytokine-transduced Stromal Cell Line
Published on: May 10, 2017
Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids
B Meibohm1, H Derendorf, H Möllmann
1Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville 32610, USA.
Objective:
Lymphocytopenia is a sensitive surrogate marker for the immunological effects of corticosteroids. This pharmacokinetic/pharmacodynamic (PK/PD) study investigated whether the circadian variation of blood lymphocytes observed after placebo is secondary to the circadian rhythm of endogenous cortisol, and developed based on this relationship an improved PK/PD model for a more sensitive description of the effect of low-dose corticosteroid therapy on blood lymphocytes considering the net activity of the exogenous corticosteroid budesonide and endogenous cortisol.
Methods:
In an open, parallel study design, 3 mg oral budesonide or placebo were given at 8.00 a.m., 4.00 p.m. and midnight to two groups of 12 volunteers. Lymphocyte counts and serum concentrations of budesonide and cortisol were monitored for 24 hours. A mechanism-based PK/PD model which considered the non-linear protein binding of cortisol and the budesonide-induced cortisol suppression was employed to relate changes in blood lymphocytes to free cortisol levels after placebo and to the net activity of free budesonide and free endogenous cortisol after active treatment.
Results:
The circadian rhythm of blood lymphocytes observed after placebo could inversely be related to the circadian rhythm of serum cortisol. After budesonide administration, lymphocyte counts could accurately be linked to the net activity of budesonide and endogenous cortisol. The resulting EC50 values for the effect of budesonide on cortisol, budesonide on lymphocytes and cortisol on lymphocytes were 0.063 +/- 0.034, 0.22 +/- 0.13 and 26.3 +/- 15.0 ng/ml (placebo group 15.4 +/- 3.4 ng/ml), respectively.
Conclusions:
The presented mechanism-based PK/PD model suggests that blood lymphocytes are under physiological control of cortisol. It further indicates that endogenous and exogenous corticosteroids and their pharmacological interaction need to be considered for modeling the effects of low doses of exogenous corticosteroids on the immune system.
Related Concept Videos
Pharmacokinetic–Pharmacodynamic Relationship: Problems
Pharmacokinetic–Pharmacodynamic Relationship: Model Components
Pharmacodynamic Models: Overview
Pharmacodynamic Models: Direct Effect Model and Indirect Response Model
Cushing Syndrome I: Introduction
Cushing Syndrome II: Pathophysiology

