Morwarid Shahhossini (1), Michael Hessler (2), Georg Hempel (1)
(1) Institute of Pharmaceutical and Medicinal Chemistry, Clinical Pharmacy, Westfälische Wilhelms-University Muenster, Corrensstr. 48, 48149 Muenster, Germany. (2) Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Muenster, Germany
Objectives: Sepsis is defined as fatal organ dysfunction caused by a dysregulated host response to infection and is associated with significant morbidity and mortality especially in critically ill patients [1]. Excessive release of cytokines is one of the hallmarks of sepsis. This leads primarily to tissue damage, metabolic acidosis and ultimately failure of multiple organs [2]. Physiologically-based pharmacokinetic (PBPK) models combine drug-specific information and previously collected knowledge about the physiology of the organism. Whole-body PBPK models contain a precise representation of organs and tissues and help to predict the pharmacokinetic behavior of drugs [3]. The objective of this study in sheep was first to estimate the amount of adsorption of antiinfectives to Cytosorb®, a device developed to remove cytokines from serum of septic patients. After data collection, the sheep should be integrated into PK-Sim® as a part of the Open Systems Pharmacology Suite and then to develop a PBPK model for sheep suffering from septic shock treated intravenous ciprofloxacin (i.v.) [4]. To evaluate the model, it was compared and adapted to the measured plasma samples.
Methods: After approval by the responsible authority, septic shock was induced in 20 sheep by inoculation of feces in the peritoneal cavity. A causal sepsis therapy was performed with ciprofloxacin, meropenem, micafungin and vancomycin. Ciprofloxacin (400mg/ 200mL) was infused as short infusion i.v. over 60 minutes. In addition, a supportive therapy with volume and vasopressors according to current guidelines was performed. Sheep were randomized into two groups. The therapy group (n=10) underwent hemadsorption and the control group (n=10) underwent a placebo procedure. During the experiment, blood samples were collected at eleven time points to determine the concentration of ciprofloxacin using HPLC. To build a PBPK model, a comprehensive literature search was performed to integrate relevant physiological data of the sheep into PK-Sim® [5], which also included qualitative and quantitative changes in the sheep during sepsis and septic shock.
Results: The literature review revealed numerous studies containing information on various physiological parameters of healthy and septic sheep. However, quantitative data on some parameters, such as metabolic enzyme activity in septic shock in sheep, were almost completely lacking. Of the organisms available in PK-Sim®, the minipig was the most suitable animal and was selected as the base organism and adapted to sheep according to available physiological data. The developed PBPK model was able to accurately describe ciprofloxacin exposure following administration of a short infusion of 400 mg/200mL, particularly in the concentration range ≥ 1 µg/L and showed minimal bias and good precision. Septic shock and hemadsorption were successfully integrated into the model.
Conclusions: It was possible to integrate the sheep as an organism into PK-Sim® and to develop a PBPK model that shows a very good prediction of ciprofloxacin blood concentrations in ovine septic shock. For further development of the model, a next step may be to integrate tissue concentrations of Ciprofloxacin into the model to describe and predict target concentrations of Ciprofloxacin at the Side of infection.
References:
[1] Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.
[2] Kogelmann K, Jarczak D, Scheller M, et al. Hemoadsorption by CytoSorb in septic patients: a case series. Crit Care. 2017 Mar 27;21(1):74.
[3] Siebinga H, de Wit-van der Veen BJ, Beijnen JH, et al. A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors. EJNMMI Res. 2021 Aug 16;11(1):73.
[4] www.open-systems-pharmacology.org.
[5] Li M, Wang YS, Elwell-Cuddy T, et al. Physiological parameter values for physiologically based pharmacokinetic models in food-producing animals. Part III: Sheep and goat. J Vet Pharmacol Ther. 2021 Jul;44(4):456-477.
Reference: PAGE 30 (2022) Abstr 10001 [www.page-meeting.org/?abstract=10001]
Poster: Drug/Disease Modelling - Absorption & PBPK