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A Whole-Body Physiologically Based Pharmacokinetic-Pharmacodynamic (WBPBPK-PD) Model for Colistin in Critically Ill Patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
4th Department of Internal Medicine, Medical School, Athens University, Athens, Greece.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objectives: Colistin is used as a salvage therapy for multidrug-resistant Gram-negative bacterial infections and administered as a prodrug, colistimethate sodium (CMS). Characterizing distribution of colistin at the site of infection is important to optimize bacterial killing. The aims of this analysis were (i) to apply a whole-body physiologically based pharmacokinetic (WPBPK) model structure to describe the pharmacokinetics (PK) of CMS and colistin in critically ill patients and (ii) to predict colistin concentration-time courses and bacterial killing in target tissues combining the WBPBPK model with a semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) model.

Methods: 27 critically ill patients treated with colistin were included in the analysis. A WBPBPK model previously developed in rat was applied to describe CMS and colistin PK data. The model was used to predict tissue concentrations in lungs, skin, blood and kidneys to drive a semi-mechanistic PKPD model on a wild-type (ATCC 27853) or a meropenem-resistant (AUR552) clinical strain P. aeruginosa to predict bacterial killing following the original dosing regimen and by replacing the original initial dose with a loading dose of 9MU.

Results: The plasma data were reasonably well described by the WBPBPK model for both CMS and colistin with a slight overprediction at the 1st occasion.  High exposure was predicted in kidneys comparable to what had been predicted in previous studies, in rat and healthy subjects. Bacterial load was quickly cleared for both the ATCC 27853 and ARU552 strains in all tissues and at a higher extend in kidney tissue, for all dosing scenarios.

Conclusion: The WPBPK model was able to adequately describe the PK of CMS and colistin in critically ill patients. The combination of the predicted PK profiles in tissues of interest with a PKPD model was able to predict the bactericidal effect of colistin at target sites.

Keyword [en]
WBPBPK-PD model, colistin, critically ill patient, bacterial killing, site of infection
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-280002OAI: oai:DiVA.org:uu-280002DiVA: diva2:909419
Available from: 2016-03-07 Created: 2016-03-07 Last updated: 2016-04-06
In thesis
1. Physiologically Based Pharmacometric Models for Colistin and the Immune Response to Bacterial Infection
Open this publication in new window or tab >>Physiologically Based Pharmacometric Models for Colistin and the Immune Response to Bacterial Infection
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotic treatment failure might be due to bacterial resistance or suboptimal exposure at target site and there is a lack of knowledge on the interaction between antimicrobial pharmacodynamics (PD) and the immune response to bacterial infections. Therefore, it is crucial to develop tools to increase the understanding of drug disposition to better evaluate antibiotic candidates in drug development and to elucidate the role of the immune system in bacterial infections.

Colistin is used as salvage therapy against multidrug resistant Gram-negative infections. In this work, a whole-body physiologically based pharmacokinetic model (WBPBPK) was developed to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in animal and human. The scalability of the model from animal to human was assessed with satisfactory predictive performance for CMS and demonstrating the need for a mechanistic understanding of colistin elimination.

The WBPBPK model was applied to investigate the impact of pathophysiological changes commonly observed in critically ill patients on tissue distribution of colistin and to evaluate different dosing strategies.

Model predicted concentrations in tissue were used in combination with a semi-mechanistic PKPD model to predict bacterial killing in tissue for two strains of Pseudomonas aeruginosa.

Finally, a toxicokinetic (TK) model was constructed to describe the time course of E. coli endotoxin concentrations in plasma and the effect on pro-inflammatory cytokine release. The model adequately described the concentration-time profiles of endotoxin and its stimulation of IL-6 and TNF-α production using an indirect response model combined with a transit compartment chain with a tolerance component to endotoxemia.

The WBPBPK model developed in this work increased the knowledge on colistin tissue exposure under various conditions and could be used in drug development process to assess antibiotic efficacy or to test new drug combinations. The model describing endotoxin TK and its effect on cytokines is a new tool to be further applied in longitudinal studies to explore the immune response cascade induced by bacterial infections. The methodology applied in this thesis contributes to the development of an integrated modeling framework including physiology, drug distribution, bacterial growth and killing as well as the immune response to infection.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 93 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 213
PBPK model, endotoxin, colistin, WBPBPK-PD, CMS, inflammation, tissue distribution, Kp, predictions in tissue, interspecies scaling
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-280208 (URN)978-91-554-9504-6 (ISBN)
Public defence
2016-04-29, B/B22, Biomedicinskt Centrun (BMC) Husargatan 3, Uppsala, 09:15 (English)
Available from: 2016-04-06 Created: 2016-03-09 Last updated: 2016-04-12

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