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  • 1.
    Bouchene, Salim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Physiologically Based Pharmacometric Models for Colistin and the Immune Response to Bacterial Infection2016Doktoravhandling, med artikler (Annet vitenskapelig)
    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.

    Delarbeid
    1. Development of a Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin methanesulfonate (CMS) in Rat
    Åpne denne publikasjonen i ny fane eller vindu >>Development of a Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin methanesulfonate (CMS) in Rat
    Vise andre…
    (engelsk)Artikkel i tidsskrift (Fagfellevurdert) Submitted
    Abstract [en]

    Colistin is a polymyxin antibiotic which is used to treat patients infected with multidrug resistant Gram negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WBPBPK) model in rat for colistin and its prodrug, CMS. The Kp prior values of colisin and CMS used in the WBPBPK model were either measured ex vivo in rat tissue homogenates or calculated using an in silico model. The PK parameters were estimated fitting plasma concentrations from rats receiving an i.v. bolus of CMS. In the WBPBPK model, the tissue distribution was assumed to be well-stirred and perfusion-limited. Three scenarios were investigated: estimating the Kp values using in silico Kp prior values (I), estimating the Kp values using the Kp prior values from ex vivo experiments (II) and fixing the Kp values to the experimental ex vivo Kp values (III). The WBPBPK model well described CMS and colistin plasma concentration-time profiles. Colistin Kp values in kidneys were higher than in the other tissues. The predicted concentrations in tissue were highest for kidneys and brain which might be due to a high affinity for these tissues and/or active transport processes that remain poorly elucidated. The clearance estimates of CMS and colistin were in agreement with previously reported values in the literature. The model developed in this study might be a valuable tool in drug development to understand the disposition of colistin or new polymyxin candidates as well as to guide for optimal dosing regimens.

    Emneord
    colistin, CMS, WBPBPK model, tissue distribution, PBPK
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-279996 (URN)
    Tilgjengelig fra: 2016-03-07 Laget: 2016-03-07 Sist oppdatert: 2018-01-10
    2. 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
    Åpne denne publikasjonen i ny fane eller vindu >>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
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    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.

    Emneord
    WBPBPK modeling, colistin, CMS, interspecies scaling, predictions in human, population approach
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-279997 (URN)
    Forskningsfinansiär
    Security Link
    Tilgjengelig fra: 2016-03-07 Laget: 2016-03-07 Sist oppdatert: 2018-01-10
    3. 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
    Åpne denne publikasjonen i ny fane eller vindu >>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
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    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.

    Emneord
    colistin, CMS, WBPBPK model, PBPK, human, predictions, urinary disposition
    HSV kategori
    Forskningsprogram
    Farmakokinetik och läkemedelsterapi
    Identifikatorer
    urn:nbn:se:uu:diva-280001 (URN)
    Tilgjengelig fra: 2016-03-07 Laget: 2016-03-07 Sist oppdatert: 2018-01-10
    4. A Whole-Body Physiologically Based Pharmacokinetic-Pharmacodynamic (WBPBPK-PD) Model for Colistin in Critically Ill Patients
    Åpne denne publikasjonen i ny fane eller vindu >>A Whole-Body Physiologically Based Pharmacokinetic-Pharmacodynamic (WBPBPK-PD) Model for Colistin in Critically Ill Patients
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    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.

    Emneord
    WBPBPK-PD model, colistin, critically ill patient, bacterial killing, site of infection
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-280002 (URN)
    Tilgjengelig fra: 2016-03-07 Laget: 2016-03-07 Sist oppdatert: 2018-01-10
  • 2.
    Bouchene, Salim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Dosne, Anne-Gaëlle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Marchand, Sandrine
    INSERM U-1070, Pôle Biologie Santé, Poitiers, France; Laboratoire de Toxicologie et Pharmacocinétique, CHU de Poitiers, Poitiers, France; UFR Medecine et Pharmacie, Poitiers, France.
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Couet, William
    INSERM U-1070, Pôle Biologie Santé, Poitiers, France; Laboratoire de Toxicologie et Pharmacocinétique, CHU de Poitiers, Poitiers, France; UFR Medecine et Pharmacie, Poitiers, France.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    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 humanManuskript (preprint) (Annet vitenskapelig)
    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.

  • 3.
    Bouchene, Salim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Couet, William
    INSERM U-1070, Pôle Biologie Santé, Poitiers, France; Laboratoire de Toxicologie et Pharmacocinétique, CHU de Poitiers, Poitiers, France; UFR Medecine et Pharmacie, Poitiers, France.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Application of a whole-body physiologically based pharmacokinetic model to describe the plasma and urine disposition of colistin and colistin methanesulfonate (CMS) in healthy volunteersManuskript (preprint) (Annet vitenskapelig)
    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.

  • 4.
    Bouchene, Salim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Plachouras, Diamantis
    4th Department of Internal Medicine, Medical School, Athens University, Athens, Greece.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A Whole-Body Physiologically Based Pharmacokinetic-Pharmacodynamic (WBPBPK-PD) Model for Colistin in Critically Ill PatientsManuskript (preprint) (Annet vitenskapelig)
    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.

  • 5.
    Bouchene, Salim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Marchand, Sandrine
    INSERM, U 1070, Pole Biol Sante, Poitiers, France;CHU Poitiers, Lab Toxicol & Pharmacocinet, Poitiers, France.
    Couet, William
    INSERM, U 1070, Pole Biol Sante, Poitiers, France;CHU Poitiers, Lab Toxicol & Pharmacocinet, Poitiers, France.
    Friberg, Lena E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gobin, Patrice
    INSERM, U 1070, Pole Biol Sante, Poitiers, France.
    Lamarche, Isabelle
    INSERM, U 1070, Pole Biol Sante, Poitiers, France.
    Gregoire, Nicolas
    INSERM, U 1070, Pole Biol Sante, Poitiers, France;CHU Poitiers, Lab Toxicol & Pharmacocinet, Poitiers, France.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat2018Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, nr 4, s. 407-422Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Colistin is a polymyxin antibiotic used to treat patients infected with multidrug-resistant Gram-negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue-to-plasma partition coefficient, K-p. Colistin and its prodrug, colistin methanesulfonate (CMS) K-p priors, were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting invivo their plasma concentration-time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a nonlinear mixed effect (NLME) modelling approach. A WB-PBPK model was developed assuming a well-stirred and perfusion-limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: K-p was estimated using in silico K-p priors (I) or K-p was estimated using experimental K-p priors (II) or K-p was fixed to the experimental values (III). The WB-PBPK model best described colistin and CMS plasma concentration-time profiles in scenario II. Colistin-predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental K-p prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico K-p priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigate the impact of disease state on colistin disposition.

  • 6.
    Bouchene, Salim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Marchand, Sandrine
    INSERM U-1070, Pôle Biologie Santé, Poitiers, France; Laboratoire de Toxicologie et Pharmacocinétique, CHU de Poitiers, Poitiers, France; UFR Medecine et Pharmacie, Poitiers, France.
    Couet, William
    INSERM U-1070, Pôle Biologie Santé, Poitiers, France; Laboratoire de Toxicologie et Pharmacocinétique, CHU de Poitiers, Poitiers, France; UFR Medecine et Pharmacie, Poitiers, France.
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gobin, Patrice
    INSERM U-1070, Pôle Biologie Santé, Poitiers, France.
    Lamarche, Isabelle
    INSERM U-1070, Pôle Biologie Santé, Poitiers, France.
    Grégoire, Nicolas
    INSERM U-1070, Pôle Biologie Santé, Poitiers, France; Laboratoire de Toxicologie et Pharmacocinétique, CHU de Poitiers, Poitiers, France.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Development of a Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin methanesulfonate (CMS) in RatArtikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Colistin is a polymyxin antibiotic which is used to treat patients infected with multidrug resistant Gram negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WBPBPK) model in rat for colistin and its prodrug, CMS. The Kp prior values of colisin and CMS used in the WBPBPK model were either measured ex vivo in rat tissue homogenates or calculated using an in silico model. The PK parameters were estimated fitting plasma concentrations from rats receiving an i.v. bolus of CMS. In the WBPBPK model, the tissue distribution was assumed to be well-stirred and perfusion-limited. Three scenarios were investigated: estimating the Kp values using in silico Kp prior values (I), estimating the Kp values using the Kp prior values from ex vivo experiments (II) and fixing the Kp values to the experimental ex vivo Kp values (III). The WBPBPK model well described CMS and colistin plasma concentration-time profiles. Colistin Kp values in kidneys were higher than in the other tissues. The predicted concentrations in tissue were highest for kidneys and brain which might be due to a high affinity for these tissues and/or active transport processes that remain poorly elucidated. The clearance estimates of CMS and colistin were in agreement with previously reported values in the literature. The model developed in this study might be a valuable tool in drug development to understand the disposition of colistin or new polymyxin candidates as well as to guide for optimal dosing regimens.

  • 7.
    Bouchene, Salim
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Marchand, Sandrine
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Björkman, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Couet, William
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Whole Body Physiologically-Based Pharmacokinetic Model for Colistin and Colistimethate Sodium (CMS) in Six Different Species: Mouse, Rat, Rabbit, Baboon, Pig and Human2013Inngår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 40, nr S1, s. S115-S116Artikkel i tidsskrift (Annet vitenskapelig)
  • 8.
    Marchand, Sandrine
    et al.
    INSERM U1070, Pole Biol Sante, F-86073 Poitiers 9, France.;Univ Poitiers, Fac Med & Pharm, F-86073 Poitiers 9, France.;CHU Poitiers, Lab Toxicol & Pharmacocinet, F-86000 Poitiers, France..
    Bouchene, Salim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    de Monte, Michele
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Guilleminault, Laurent
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Montharu, Jerome
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Cabrera, Maria
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Gregoire, Nicolas
    INSERM U1070, Pole Biol Sante, F-86073 Poitiers 9, France.;Univ Poitiers, Fac Med & Pharm, F-86073 Poitiers 9, France..
    Gobin, Patrice
    INSERM U1070, Pole Biol Sante, F-86073 Poitiers 9, France.;CHU Poitiers, Lab Toxicol & Pharmacocinet, F-86000 Poitiers, France..
    Diot, Patrice
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Couet, William
    INSERM U1070, Pole Biol Sante, F-86073 Poitiers 9, France.;Univ Poitiers, Fac Med & Pharm, F-86073 Poitiers 9, France.;CHU Poitiers, Lab Toxicol & Pharmacocinet, F-86000 Poitiers, France..
    Vecellio, Laurent
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS Nebulisation in Baboon Monkeys2015Inngår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 32, nr 10, s. 3403-3414Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The objective of this study was to compare two different nebulizers: Eflow rapidA (R) and Pari LC starA (R) by scintigraphy and PK modeling to simulate epithelial lining fluid concentrations from measured plasma concentrations, after nebulization of CMS in baboons. Three baboons received CMS by IV infusion and by 2 types of aerosols generators and colistin by subcutaneous infusion. Gamma imaging was performed after nebulisation to determine colistin distribution in lungs. Blood samples were collected during 9 h and colistin and CMS plasma concentrations were measured by LC-MS/MS. A population pharmacokinetic analysis was conducted and simulations were performed to predict lung concentrations after nebulization. Higher aerosol distribution into lungs was observed by scintigraphy, when CMS was nebulized with Pari LCA (R) star than with Eflow RapidA (R) nebulizer. This observation was confirmed by the fraction of CMS deposited into the lung (respectively 3.5% versus 1.3%).CMS and colistin simulated concentrations in epithelial lining fluid were higher after using the Pari LC starA (R) than the Eflow rapidA (R) system. A limited fraction of CMS reaches lungs after nebulization, but higher colistin plasma concentrations were measured and higher intrapulmonary colistin concentrations were simulated with the Pari LC StarA (R) than with the Eflow RapidA (R) system.

  • 9.
    Thorsted, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bouchene, Salim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Tano, Eva
    Section of Clinical Microbiology and Infectious Medicine, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Castegren, Markus
    Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Lipcsey, Miklos
    Hedenstierna laboratory, Section of Anesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Sjölin, Jan
    Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden; Hedenstierna laboratory, Section of Anesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nielsen, Elisabet I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Toxicokinetics of Endotoxin and its relation to Pro-Inflammatory Cytokines Tumor Necrosis Factor α (TNF-α) and Interleukin-6 (IL-6) in a Pig sepsis modelManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background and purpose: Infection with Gram-negative bacteria and the immune system’s subsequent recognition of the potent membrane-bound activator endotoxin (ETX), can lead to persistent immune activation. The purpose of the current work was to develop a model-based description of the time-course of ETX concentrations and its effect on the release of the pro-inflammatory, cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6).

    Methods: Non-linear mixed effects models were developed based on data from experimental studies in a porcine model of sepsis. Intravenous infusions of E. coli ETX were administered to the piglets at different doses and durations of infusion. ETX, TNF-α and IL-6 plasma levels were measured throughout the infusion time.

    Results: The concentration-time profile of ETX was well described with a one-compartment model with non-linear elimination. Observation of contamination in early ETX measurements was handled by initializing the central compartment to an estimated parameter. The concentration of ETX over time was used as the driver of the inflammatory response. An indirect response model with ETX stimulated production (Emax model), delayed through a transit chain (three compartments) was used to describe the observed cytokine concentration-time profiles. To describe tolerance to ETX exposure, an exponential time-dependent increase was added to the parameter describing the potency of ETX to stimulate cytokine release (EC50).

    Conclusions: A mathematical model was developed to depict the time-course of ETX in plasma and its 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

  • 10.
    Thorsted, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bouchene, Salim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Tano, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionsmedicin. Uppsala Univ Hosp, Sect Clin Microbiol & Infect Med, Dept Med Sci, Uppsala, Sweden.
    Castegren, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar. Karolinska Univ Hosp, Div Perioperat Med & Intens Care, Stockholm, Sweden;Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Lipcsey, Miklós
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. Uppsala Univ Hosp, Dept Surg Sci, Sect Anesthesiol & Intens Care, Hedenstierna Lab, Uppsala, Sweden.
    Sjölin, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar. Uppsala Univ Hosp, Infect Dis Sect, Dept Med Sci, Uppsala, Sweden.
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nielsen, Elisabet I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-62019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 2, artikkel-id e0211981Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111: B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 mu g/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-alpha to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-alpha concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-alpha production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-a, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-alpha and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.

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