Pharmacokinetic/Pharmacodynamic Modeling of Total Lymphocytes and Selected Subtypes After Oral Budesonide

In the present pharmacokinetic/pharmacodynamic (PK/PD) evaluation, cortisol, total lymphocytes, and lymphocyte subpopulations were monitored following single oral doses of two oral formulations of 3mg budesonide (BUD )( Dosage Forms A and B) in order to assess the differential effects that BUD may have on cortisol suppression and the modulation of blood lymphocyte subtypes. On a single occasion, five subjects received one 3mg capsule of Dosage Form A, four received three capsules of Dosage Form A (single dose of 9mg), and five received three capsules of Dosage Form B (single dose of 9mg). Placebo capsules were administered to six subjects in the study. Cortisol concentrations, total lymphocyte counts, and lymphocyte subpopulation counts for the CD3, CD4, CD8, CD19, and CD56/16 were fitted to an in direct PK/PD response model that described the effects of BUD on serum cortisol concentrations as well as the combined effects of BUD and cortisol on total lymphocytes and the CD3, CD4, CD8, CD19, and CD56/16 subtypes. Data were also analyzed using noncompartmental methods. The PK/PD model fitted the data with the exception of data for CD56/16. The IC50 value for unbound BUD acting on total lymphocytes was 0.276ng/ml while the IC50 values for unbound BUD acting on lymphocyte subtypes ranged from 0.150ng/ml for CD4 to 0.364ng/ml for CD8. The IC50 values for the effects of BUD on serum cortisol were lower (0.079ng/ml). The results of PK/PD modeling and noncompartmental analysis indicate that BUD has a smaller effect on the CD8 subtype and larger effects on the CD4 and CD19 subtypes, relative to the effect on total lymphocytes, and that cortisol suppression, although not a direct immunological biomarker, may be a more sensitive marker for the systemic effect of corticosteroids.