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Pharmacokinetic‐pharmacodynamic modeling of the inhibitory effect of erythromycin on tumour necrosis factor‐α and interleukin‐6 production
Author(s) -
Guchelaar HenkJan,
Schultz Marc J.,
Van Der Poll Tom,
Koopmans Richard P.
Publication year - 2001
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1046/j.1472-8206.2001.00054.x
Subject(s) - erythromycin , dose , pharmacology , pharmacokinetics , streptococcus pneumoniae , tumor necrosis factor alpha , in vivo , cytokine , pharmacodynamics , ec50 , dose–response relationship , stimulation , medicine , chemistry , antibiotics , biology , in vitro , biochemistry , microbiology and biotechnology
Erythromycin inhibits the production of tumour necrosis factor‐alpha (TNF‐α) and interleukin‐6 (IL6) induced by heat‐killed Streptococcus pneumoniae in human whole blood ex‐vivo. The objective of the present study was to determine and characterize the concentration–effect relationship of this phenomenon in order to predict its possible clinical relevance. Six healthy volunteers received a single intravenous dose of 1000 mg erythromycin. Blood samples were obtained up to 4 h after drug administration. Samples were assayed for erythromycin concentrations and (after heat‐killed Streptococcus pneumoniae stimulation) for TNF‐α and IL6 concentrations. Effect vs. time data from individual subjects were fitted to the indirect response model with an Emax concentration–effect relationship. Simulations of these effects were performed for therapeutic intravenous and oral erythromycin dosage regimens. The geometric means of the values of Kin, Kout and EC50 were 15.4 μg/h, 0.82/h, 9.4 mg/L for TNF‐α and 321 μg/h, 2.02/h, 18.3 mg/L for IL6. Simulations revealed a maximal inhibition of TNF‐α concentrations of 35%, 50%, 16% and 27% at erythromycin dosages of 500 mg iv, 1000 mg iv, 500 mg p.o and 1000 mg p.o. q 6 h, respectively, whereas a maximal inhibition of IL6 of 29%, 44%, 13% and 22% are predicted for the respective regimens. The inhibitory effect of erythromycin on TNF‐α and IL6 production can be adequately described by the indirect response model with an Emax concentration–effect relationship. Simulations predicted a substantial decrease of production of these cytokines at intravenous and to a much lesser extent at oral erythromycin dosage regimens.