Pharmacokinetic‐pharmacodynamic modeling of the inhibitory effect of erythromycin on tumour necrosis factor‐α 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.

Pharmacokinetic/Pharmacodynamic Modelling of Roxithromycin for the Inhibitory Effect of Tumour Necrosis Factor‐Alpha and Interleukin‐6 Production in Dogs

“…Indeed, this is physiologically the most reasonable explanation, because roxithromycin acts by inhibition of mRNA transcription (Suzaki et al., 1999). This finding was in agreement with Guchelaar et al.’s (2001) report on the inhibitory effect of erythromycin on TNF‐ α and IL‐6 production in human.…”

“…To account for the apparent time delay between the observed plasma roxithromycin concentration profiles and the development of the TNF‐ α and IL‐6 response in time, the PK/PD relationship was described using a model for indirect response, as proposed by Guchelaar et al. (2001).…”

Population Pharmacokinetics of Azithromycin in Whole Blood, Peripheral Blood Mononuclear Cells, and Polymorphonuclear Cells in Healthy Adults

“…Interestingly, there is no clear in vitro / in vivo correlation, and short‐term direct effects on PMNs cannot explain the fact that in chronic inflammatory conditions, weeks to months of macrolide therapy appears to be required for symptomatic improvement 8 . For example, a pharmacokinetic (PK)/pharmacodynamic (PD) model predicting inhibition of interleukin‐6 and tumor necrosis factor‐α after high intravenous doses of erythromycin 9 predicts little or no inhibition of interleukin‐6 and tumor necrosis factor‐α at 250 mg once daily, a dose that produces reductions in exacerbations of bronchiectasis 10 …”