Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability.
OBJECTIVE
To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model that characterizes the effects of major systemic corticosteroids on lymphocyte trafficking and responsiveness.


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.
Hong
Ying
Y
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 543 Hochstetter Hall, Buffalo, New York 14260, USA.
Mager
Donald E
DE
Blum
Robert A
RA
Jusko
William J
WJ
D000305:Adrenal Cortex Hormones / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation; D018592:Cross-Over Studies; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D008962:Models, Theoretical; D010919:Placebos
D000305:Adrenal Cortex Hormones; D010919:Placebos