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 (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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Acknowledgments
The authors thank Dr. Robert J. Bauer (XOMA LLC, Berkeley, CA), Dr. Olanrewaju Okusanya, and Dr. Alan Forrest (Department of Pharmacy Practice, University at Buffalo, SUNY) for their assistance with S-ADAPT, Dr. Sheren X. Lin and Dr. Christian D. Lates for their clinical support of our previous study, and Ms. Nancy Pyszczynski and Ms. Suzette Mis for providing technical assistance. This research was supported, in part, by NIH Grants GM24211 and GM57980 (to WJJ), new investigator support from the University at Buffalo, SUNY (to DEM), and the University at Buffalo-Pfizer Strategic Alliance Fellowship (for YH).
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Hong, Y., Mager, D.E., Blum, R.A. et al. Population Pharmacokinetic/Pharmacodynamic Modeling of Systemic Corticosteroid Inhibition of Whole Blood Lymphocytes: Modeling Interoccasion Pharmacodynamic Variability. Pharm Res 24, 1088–1097 (2007). https://doi.org/10.1007/s11095-006-9232-x
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DOI: https://doi.org/10.1007/s11095-006-9232-x