A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6

PloS One
Anders ThorstedElisabet I Nielsen

Abstract

Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111:B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 μg/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-α to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-α concentration with continued infusion of endotoxin, was also driven by endotoxin as a c...Continue Reading

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Citations

Feb 10, 2021·Clinical Pharmacology and Therapeutics·Linda B S AulinJ G Coen van Hasselt
Feb 9, 2021·Clinical Pharmacology and Therapeutics·Craig R RaynerKaren Rowland-Yeo
Jul 22, 2021·Antibody Therapeutics·Dean BottinoArijit Chakravarty

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Methods Mentioned

BETA
Assay
enzyme-linked immunosorbent assay

Software Mentioned

tidyr
Scientific Linux
ggplot2
DuoSet
R
xpose4
NONMEM

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