Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids.
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.
Meibohm
B
B
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville 32610, USA.
Derendorf
H
H
Möllmann
H
H
Fröhlich
P
P
Tromm
A
A
Wagner
M
M
Homrighausen
S
S
Krieg
M
M
Hochhaus
G
G
D000893:Anti-Inflammatory Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019819:Budesonide / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002940:Circadian Rhythm; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006854:Hydrocortisone / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018655:Lymphocyte Count / Q000187:drug effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008231:Lymphopenia / Q000139:chemically induced*; D008954:Models, Biological; D010919:Placebos; D011485:Protein Binding
D000893:Anti-Inflammatory Agents; D010919:Placebos; D019819:Budesonide; D006854:Hydrocortisone