title: Pharmacokinetic-pharmacodynamic modeling of the inhibitory effect of erythromycin on tumour necrosis factor-alpha and interleukin-6 production.
abstract: Erythromycin inhibits the production of tumour necrosis factor-alpha (TNF-alpha) 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-alpha 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 microg/h, 0.82/h, 9.4 mg/L for TNF-alpha and 321 microg/h, 2.02/h, 18.3 mg/L for IL6. Simulations revealed a maximal inhibition of TNF-alpha concentrations of 35%, 50%, 16% and 27% at erythromycin dosages of 500 mg i.v., 1000 mg i.v., 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-alpha 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.
authors.affiliation: Department of Pharmacy, Academic Medical Center, University of Amsterdam, Meibergdreef 9, NL 1105 AZ Amsterdam, The Netherlands. H.J.GUCHELAAR@AMC.UVA.NL
authors.forename: H J
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: M J
authors.initials: MJ
authors.lastname: Schultz
authors.forename: T
authors.initials: T
authors.lastname: van der Poll
authors.forename: R P
authors.initials: RP
authors.lastname: Koopmans
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004917:Erythromycin / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000096:biosynthesis*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D000093242:Interleukin-6 Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D004917:Erythromycin; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors