uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Application of a whole-body physiologically based pharmacokinetic model to describe the plasma and urine disposition of colistin and colistin methanesulfonate (CMS) in healthy volunteers
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
INSERM U-1070, Pôle Biologie Santé, Poitiers, France; Laboratoire de Toxicologie et Pharmacocinétique, CHU de Poitiers, Poitiers, France; UFR Medecine et Pharmacie, Poitiers, France.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objectives: The primary aim of this work was to develop a whole-body physiologically based pharmacokinetic (WBPBPK) model to describe CMS and colistin disposition in human plasma and urine. The secondary aim of this analysis was to use the WBPBPK model to predict CMS and colistin tissue distribution in typical individuals with different pathophysiological changes and receiving different dosing regimens.

Methods: Twelve healthy males were included in the analysis. They received a single dose of 80 mg CMS (1 million unit) through a 1-h intravenous infusion. Venous blood was collected between 0 and 18 h post dose. Fractionated urine samples were collected between 0 and 24 h after dose. A WBPBPK model initially developed in rat was further detailed with the addition of a specific urinary tract (UT) model. The Kp values of CMS and colistin were estimated for all tissues using experimental Kp prior values from rat tissue homogenates.

Results: The model adequately described CMS and colistin concentrations over time in plasma and in urine. A shared first order elimination rate constant was estimated to depict the hydrolysis of CMS in plasma and tissues. A separate hydrolysis rate constant for CMS was estimated in urine, and was lower than in plasma and tissues. A shared non-renal elimination rate constant of colistin was estimated in plasma and in tissues. CMS and colistin disposition in urine was well characterized by the UT model. The tubular reabsorption of colistin was best described by a saturable model estimating the colistin affinity constant, KM. Non-specific binding of colistin in the UT lumen was accounted for using a linear relationship.

Conclusion: The WBPBPK developed in this study characterized plasma and urine PK of CMS and colistin in human well. This model was used as a new framework to predict colistin exposure in the tissues of interest under different physiological conditions. The model can be easily refined when new data are available and can be combined to PKPD models to increase the understanding of the concentration-effect relationship at target sites.

Keyword [en]
colistin, CMS, WBPBPK model, PBPK, human, predictions, urinary disposition
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
URN: urn:nbn:se:uu:diva-280001OAI: oai:DiVA.org:uu-280001DiVA: diva2:909417
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

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Bouchene, Salim
By organisation
Department of Pharmaceutical Biosciences
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 72 hits
ReferencesLink to record
Permanent link

Direct link