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Individualizing combination of two antiproliferative immunosuppressants with pharmacodynamic modeling of stimulated lymphocyte responses
Author(s) -
Berry Vishal,
Magill Amy,
Yost Mary,
Janosky Janine,
Sindhi Rakesh
Publication year - 2006
Publication title -
cytometry part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.316
H-Index - 90
eISSN - 1552-4930
pISSN - 1552-4922
DOI - 10.1002/cyto.a.20200
Subject(s) - pharmacology , ionomycin , population , pharmacodynamics , lymphocyte , calcineurin , il 2 receptor , t cell , flow cytometry , chemistry , immunology , medicine , pharmacokinetics , intracellular , immune system , transplantation , biochemistry , environmental health
Background Unpredictable serious adverse events (SAE) of immunosuppression, e.g. nephrotoxicity, with the nephrotoxic immunosuppressants have fostered interest in alternative regimens, which contain two antiproliferative agents, and individualized therapy. However, titration of such combinations to individual needs is not understood. Specific Aim To determine concentration (C) mixtures of mycophenolate mofetil (MMF) and sirolimus (SRL), which produce half‐maximal inhibitory effect (EC 50 ) on human lymphocytes from individual subjects. Methods Concentration mixtures of MMF (0–5 μg/ml) and SRL (0–30 ng/ml) were incubated with whole blood from each of five healthy human subjects. The intracellular cytokines IL‐2, TNF‐α, and IFN‐γ were measured in PMA‐ionomycin‐stimulated T‐cells (CD4+), while CD54, CD95, CD86, CD25, CD69, and CD71 were measured in pokeweed mitogen‐stimulated B‐cells, by flow cytometry. Pharmacodynamic (PD) relationships were evaluated using Hill equations modified for single and multidrug regimens, and expressed as EC 50 for each target receptor. Results No change was seen in the expression of the T‐cell cytokines with either MMF or SRL. Each B‐cell receptor was inhibited with increasing concentrations of either MMF or SRL. Each B‐cell receptor was also inhibited half‐maximally at lower concentrations of MMF in the presence of SRL, than with either agent alone, for the test population of five subjects together, and for each of five individual subjects. However, each subject showed distinctly different amounts of MMF and SRL that needed to be present together, in order to produce an identical inhibitory effect on lymphocyte function. Conclusions PD analysis of biological effect can potentially predict optimal concentration mixtures of two immunosuppressants for individual recipients, and enhance rejection prophylaxis and safety. While this holds promise for drug development efforts, clinical application must await correlation of lymphocyte markers with post‐transplant clinical outcomes. © 2005 Wiley‐Liss, Inc.