Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids

Objective: Lymphocytopenia is a sensitive surrogate marker for the immunolo gical 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 t herapy on blood lymphocytes considering the net activity of the exogenous c orticosteroid budesonide and endogenous cortisol. Methods: In an open, para llel 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 a nd serum concentrations of budesonide and cortisol were monitored for 24 ho urs. A mechanism-based PK/PD model which considered the non-linear protein binding of cortisol and the budesonide-induced cortisol suppression was emp loyed to relate changes in blood lymphocytes to free cortisol levels after placebo and to the net activity of free budesonide and free endogenous cort isol after active treatment. Results: The circadian rhythm of blood lymphoc ytes observed after placebo could inversely be related to the circadian rhy thm of serum cortisol. After budesonide administration, lymphocyte counts c ould accurately be linked to the net activity of budesonide and endogenous cortisol. The resulting EC50 Values for the effect of budesonide on cortiso l, budesonide on lymphocytes and cortisol on lymphocytes were 0.063 +/- 0.0 34, 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 sugg ests 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.