Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability

Abstract

Purpose: To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model that characterizes the effects of major systemic corticosteroids on lymphocyte trafficking and responsiveness.

Materials and methods: Single, presumably equivalent, doses of intravenous hydrocortisone (HC), dexamethasone (DEX), methylprednisolone (MPL), and oral prednisolone (PNL) were administered to five healthy male subjects in a five--way crossover, placebo--controlled study. Measurements included plasma drug and cortisol concentrations, total lymphocyte counts, and whole blood lymphocyte proliferation (WBLP). Population data analysis was performed using a Monte Carlo-Parametric Expectation Maximization algorithm.

Results: The final indirect, multi-component, mechanism-based model well captured the circadian rhythm exhibited in cortisol production and suppression, lymphocyte trafficking, and WBLP temporal profiles. In contrast to PK parameters, variability of drug concentrations producing 50% maximal immunosuppression (IC(50)) were larger between subjects (73-118%). The individual log-transformed reciprocal posterior Bayesian estimates of IC(50) for ex vivo WBLP were highly correlated with those determined in vitro for the four drugs (r ( 2 ) = 0.928).

Conclusions: The immunosuppressive dynamics of the four corticosteroids was well described by the population PK/PD model with the incorporation of inter-occasion variability for several model components. This study provides improvements in modeling systemic corticosteroid effects and demonstrates greater variability of system and dynamic parameters compared to pharmacokinetics.

Fig. 1

Mechanism-based pharmacokinetic–pharmacodynamic model of systemic corticosteroids. Symbols are defined in the text.

Fig. 2

Time course of observed (symbols) and individual predicted (solid lines) plasma corticosteroid concentrations after single doses of iv dexamethasone (6 mg), methylprednisolone (30 mg), and oral prednisolone (38 mg) in one representative subject.

Fig. 3

Time course of observed (symbols) and individual predicted (solid lines) plasma Cortisol concentrations after single doses of iv hydrocortisone (150 mg), dexamethasone, methylprednisolone, and oral prednisolone in the same subject as shown in Fig. 2.

Fig. 4

Time course of observed (symbols) and individual predicted (solid lines) total lymphocyte counts after single doses of placebo, iv hydrocortisone, dexamethasone, methylprednisolone, and oral prednisolone in the same subject as shown in Figs. 2 and 3. Placebo profiles are represented by open circles and a dashed line

Fig. 5

Time course of observed (symbols) and individual predicted (solid lines) ex vivo whole blood lymphocyte proliferation after single doses of iv hydrocortisone, dexamethasone, methylprednisolone, and oral prednisolone in the same subject as shown in Figs. 2, 3 and 4.

Fig. 6

Correlation between log-transformed reciprocal individual posterior Bayesian estimates of drug potency (1/IC₅₀) for ex vivo whole blood lymphocyte proliferation in subject 1(●), subject 2 (○), subject 3 (▲), subject 4 (△), and subject 5 (▽) and those determined in vitro (r² = 0.928).

Fig. 7

Individual posterior Bayesian parameter estimates for subject 1(●), subject 2 (○), subject 3 (▲), subject 4 (△), and subject 5 (▽) in each study period. PL represents the placebo control.