Anders Thorsted (1), Salim Bouchene (1), Eva Tano (2), Markus Castegren (2), Miklos Lipcsey (2), Jan Sjölin (3), Mats O. Karlsson (1), Lena E. Friberg (1) and Elisabet I. Nielsen (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala Sweden, (2) Department of Medical Sciences, Uppsala University, Uppsala, Sweden, (3) Department of Surgical Sciences, Uppsala University, Sweden
Objectives: Infection with Gram-negative bacteria and the immune system’s subsequent recognition of the potent membrane-bound activator, endotoxin (ETX), leads to immune activation. The purpose of the work was to develop a model-based description of the toxicokinetics of ETX and its induction of the cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6).
Methods: Based on data from experimental studies, a non-linear mixed effects model was developed in NONMEM 7.3. The modelled data arose from six experimental studies of varying length (6–30 h) in an anesthetized piglet model (n=116), with the aim of studying the inflammatory host response following ETX exposure [1-6]. Generally, E. coli ETX was infused intravenously for different periods of time in rates ranging from 0.063 to 16.0 μg/kg/h. The studies examined ETX tolerance development (dampened response upon re-exposure), differences in response following different infusion regimens, and the ETX exposure-response.
Results: The time-course of ETX could be described using a one-compartment model with linear elimination (half-life of 0.48 h). Contamination in some early ETX measurements was handled with a mixture model with initialization of the central compartment to an estimated parameter for the contaminated population. For cytokines, an indirect response model with ETX stimulated production (Emax model), was used to describe the shape of the observed cytokine profiles (with a transit chain delaying IL-6). To describe tolerance development, a concentration-driven increase in the parameter describing potency (EC50) was incorporated. The increase was driven by ETX, with the extent of tolerance parameterized as an Emax relationship. Rapid tolerance development was identified and the developed model was able to describe both the initial tolerance and dampened responses upon a second exposure to a higher ETX load. In addition to the tolerance model described above previously published tolerance models were tested [7], but none were found to better describe the data.
Conclusions: A mathematical description was developed for the time-course of ETX following intravenous infusion, and linked to induction of the two immune response markers TNF-α and IL-6. This model-based approach is unique in its description of the three time-courses, and may later be expanded to better understand immune cell release in bacterial infections and sepsis-type pathophysiological changes.
References:
[1] Lipcsey M, Larsson A, Eriksson MB, Sjölin J. Inflammatory, coagulatory and circulatory responses to logarithmic increases in the endotoxin dose in the anaesthetized pig. J Endotoxin Res. 2006;12(2):99-112.
[2] Carlsson M, Lipcsey M, Larsson A, Tano E, Rubertsson S, Eriksson M, Sjolin J. Inflammatory and circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic shock–a model of endotoxin elimination. Crit Care Med. 2009 Mar;37(3):1031-e4.
[3] Lipcsey M, Larsson A, Eriksson MB, Sjölin J. Effect of the administration rate on the biological responses to a fixed dose of endotoxin in the anesthetized pig. Shock. 2008 Feb;29(2):173-80.
[4] Castegren M, Skorup P, Lipcsey M, Larsson A, Sjolin J. Endotoxin tolerance variation over 24 h during porcine endotoxemia: association with changes in circulation and organ dysfunction. PLoS One. 2013;8(1):e53221.
[5] Castegren M, Lipcsey M, Söderberg E, Skorup P, Eriksson M, Larsson A, Sjölin J. Differences in organ dysfunction in endotoxin-tolerant pigs under intensive care exposed to a second hit of endotoxin. Shock. 2012 May;37(5):501-10.
[6] Goscinski G, Lipcsey M, Eriksson M, Larsson A, Tano E, Sjölin J. Endotoxin neutralization and anti-inflammatory effects of tobramycin and ceftazidime in porcine endotoxin shock. Crit Care. 2004 Feb;8(1):R35-41.
[7] Gårdmark M, Brynne L, Hammarlund-Udenaes M, Karlsson MO. Interchangeability and predictive performance of empirical tolerance models. Clin Pharmacokinet. 1999 Feb;36(2):145-67.Acknowledgements: The research leading to the modelling results was partly supported by the Swedish Foundation for Strategic Research (SFF).
Reference: PAGE 25 () Abstr 5966 [www.page-meeting.org/?abstract=5966]
Poster: Drug/Disease modeling - Infection