Ying Hong1, Donald E Mager, Robert A Blum, William J Jusko. 1. 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.
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.
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.
Authors: Diane R Mould; Richard N Upton; Jessica Wojciechowski; Becky L Phan; Stacy Tse; Marla C Dubinsky Journal: AAPS J Date: 2018-06-14 Impact factor: 4.009