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

Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability. Research Abstract Details 

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

Ying Hong,Donald E Mager,Robert A Blum,William J Jusko,

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.

Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability. Publishing Authors By Initials

Y Hong,DE Mager,RA Blum,WJ Jusko,

For similar pharmaceutical preparations: placebos research abstracts see: pharmaceutical preparations: placebos research

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

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Pharmaceutical research

VOLUME: 24

Page Numbers: 1088-97

Journal Abbreviation: Pharm. Res.

ISSN: 0724-8741

DAY: 24

MONTH: 03

YEAR: 2007

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

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LANGUAGE: eng

NlmUniqueID: 8406521

Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability. Keywords Mesh Terms:

KEYWORDS: Placebos

MESH TERMS: drug effects

Chemical & Substance for Abstract: Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability. Information

Substance Name: Placebos

Registry Number: 0

Grant and Affiliation Information for Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability.

AFFILIATION: 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.

Country: United States

AGENCY: United States NIGMS

GRANT: GM57980

ACRONYM: GM

MEDLINETA: Pharm Res

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