Journal
PHARMACEUTICAL RESEARCH
Volume 24, Issue 6, Pages 1088-1097Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-006-9232-x
Keywords
corticosteroids; mathematical modeling; pharmacodynamics; pharmacokinetics
Funding
- NIGMS NIH HHS [R37 GM024211, R01 GM057980, GM24211, GM57980] Funding Source: Medline
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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 (IC50) were larger between subjects (73-118%). The individual log-transformed reciprocal posterior Bayesian estimates of IC50 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.
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