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Development of an interspecies whole-body physiologically based pharmacokinetic (WBPBPK) model for colistin methanesulfonate (CMS) and colistin in five animal species and evaluation of its predictive ability in human
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.
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]

Background and purpose

Colistin is a last-line antibiotic administered as the prodrug colistin methanesulfonate (CMS) for the treatment of multidrug resistant Gram-negative bacterial infections. Whole-body physiologically based pharmacokinetic (WBPBPK) models are valuable tools to understand and characterize drug disposition, predict tissue distribution and interpret exposure-response relationship. The aim of this work was to develop a WBPBPK model for colistin and CMS in five animal species and evaluate the utility of the model for predicting colistin and CMS disposition in human.

Methods

A nonlinear mixed-effects WBPBPK model previously developed in rats was extended to describe CMS and colistin plasma data of animals from 5 different species (40 mice, 6 rats, 3 rabbits, 3 baboons and 2 pigs) that had received single doses of CMS. CMS renal clearance and hydrolysis to colistin were allometrically scaled based on glomerular filtration rate (GFR) and tissue volumes, respectively. For the non-renal colistin clearance, three scaling models were evaluated: volume based allometric scaling, volume and maximum lifespan potential (MLP) based allometric scaling, and estimation of specie-specific parameters. Tissue concentrations were predicted for all species. The WBPBPK model was then used to predict human plasma concentrations, which were compared to observed human plasma PK data extracted from literature.

Results

The description of the plasma PK of CMS and colistin in mice, rats, rabbits, baboons and pigs was satisfactory. The volume and MLP based allometric scaling of the non-renal clearance of colistin was best at characterizing colistin concentration-time course, even if a misprediction remained in pigs. In human however, allometric scaling without MLP was closest to the observed data, with satisfactory prediction of the CMS plasma profiles and a slight overprediction of colistin plasma PK profiles.

Conclusions

Interspecies WBPBPK models were developed to describe the disposition of CMS and colistin across five animal species and human plasma concentrations of CMS and colistin were predicted in the right ranges.

Keyword [en]
WBPBPK modeling, colistin, CMS, interspecies scaling, predictions in human, population approach
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-279997OAI: oai:DiVA.org:uu-279997DiVA: diva2:909416
Funder
Security Link
Available from: 2016-03-07 Created: 2016-03-07 Last updated: 2016-10-20
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 213
Keyword
PBPK model, endotoxin, colistin, WBPBPK-PD, CMS, inflammation, tissue distribution, Kp, predictions in tissue, interspecies scaling
National Category
Pharmaceutical Sciences
Identifiers
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)
Opponent
Supervisors
Available from: 2016-04-06 Created: 2016-03-09 Last updated: 2016-04-12
2. Improved Methods for Pharmacometric Model-Based Decision-Making in Clinical Drug Development
Open this publication in new window or tab >>Improved Methods for Pharmacometric Model-Based Decision-Making in Clinical Drug Development
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pharmacometric model-based analysis using nonlinear mixed-effects models (NLMEM) has to date mainly been applied to learning activities in drug development. However, such analyses can also serve as the primary analysis in confirmatory studies, which is expected to bring higher power than traditional analysis methods, among other advantages. Because of the high expertise in designing and interpreting confirmatory studies with other types of analyses and because of a number of unresolved uncertainties regarding the magnitude of potential gains and risks, pharmacometric analyses are traditionally not used as primary analysis in confirmatory trials.

The aim of this thesis was to address current hurdles hampering the use of pharmacometric model-based analysis in confirmatory settings by developing strategies to increase model compliance to distributional assumptions regarding the residual error, to improve the quantification of parameter uncertainty and to enable model prespecification.

A dynamic transform-both-sides approach capable of handling skewed and/or heteroscedastic residuals and a t-distribution approach allowing for symmetric heavy tails were developed and proved relevant tools to increase model compliance to distributional assumptions regarding the residual error. A diagnostic capable of assessing the appropriateness of parameter uncertainty distributions was developed, showing that currently used uncertainty methods such as bootstrap have limitations for NLMEM. A method based on sampling importance resampling (SIR) was thus proposed, which could provide parameter uncertainty in many situations where other methods fail such as with small datasets, highly nonlinear models or meta-analysis. SIR was successfully applied to predict the uncertainty in human plasma concentrations for the antibiotic colistin and its prodrug colistin methanesulfonate based on an interspecies whole-body physiologically based pharmacokinetic model. Lastly, strategies based on model-averaging were proposed to enable full model prespecification and proved to be valid alternatives to standard methodologies for studies assessing the QT prolongation potential of a drug and for phase III trials in rheumatoid arthritis.

In conclusion, improved methods for handling residual error, parameter uncertainty and model uncertainty in NLMEM were successfully developed. As confirmatory trials are among the most demanding in terms of patient-participation, cost and time in drug development, allowing (some of) these trials to be analyzed with pharmacometric model-based methods will help improve the safety and efficiency of drug development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 91 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 223
Keyword
pharmacometrics, nonlinear mixed-effects models, confirmatory trials, residual error modeling, parameter uncertainty, sampling importance resampling, model-averaging
National Category
Health Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-305697 (URN)978-91-554-9734-7 (ISBN)
Public defence
2016-12-09, B/A1:107a, Biomedicinskt Centrum, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-11-18 Created: 2016-10-20 Last updated: 2016-11-28

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