A Population WB-PBPK Model of Colistin and its Prodrug CMS in Pigs: Focus on the Renal Distribution and Excretion

  • Alexis Viel
  • Jérôme Henri
  • Salim Bouchène
  • Julian Laroche
  • Jean-Guy Rolland
  • Jacqueline Manceau
  • Michel Laurentie
  • William Couet
  • Nicolas GrégoireEmail author
Research Paper



The objective was the development of a whole-body physiologically-based pharmacokinetic (WB-PBPK) model for colistin, and its prodrug colistimethate sodium (CMS), in pigs to explore their tissue distribution, especially in kidneys.


Plasma and tissue concentrations of CMS and colistin were measured after systemic administrations of different dosing regimens of CMS in pigs. The WB-PBPK model was developed based on these data according to a non-linear mixed effect approach and using NONMEM software. A detailed sub-model was implemented for kidneys to handle the complex disposition of CMS and colistin within this organ.


The WB-PBPK model well captured the kinetic profiles of CMS and colistin in plasma. In kidneys, an accumulation and slow elimination of colistin were observed and well described by the model. Kidneys seemed to have a major role in the elimination processes, through tubular secretion of CMS and intracellular degradation of colistin. Lastly, to illustrate the usefulness of the PBPK model, an estimation of the withdrawal periods after veterinary use of CMS in pigs was made.


The WB-PBPK model gives an insight into the renal distribution and elimination of CMS and colistin in pigs; it may be further developed to explore the colistin induced-nephrotoxicity in humans.

Key Words

colistin CMS kidneys PBPK model pigs 



Absorption, distribution, metabolism, excretion


Below the limit of quantification


Body weight


Colistin base activity


Colistimethate sodium


Observed value


Unbound fraction


Glomerular filtration rate


Gastro-intestinal tract


High-performance liquid chromatography coupled with tandem mass spectrometry


Interindividual variability




Individual prediction




Limit of quantification


Maximal residue limits


Nonlinear mixed effects


Objective function value


Physiologically-based pharmacokinetic




Population prediction


Residual variability


Sampling importance resampling




Visual predictive checks


Whole body physiologically-based pharmacokinetic


Withdrawal period

Supplementary material

11095_2018_2379_Fig11_ESM.gif (71 kb)
Figure S1

Goodness-of-fit plots for model validation. Population predicted (PRED) versus observed concentrations or quantities (DV) in log-log scale (A) and linear scale (B). Individual predicted (PRED) versus observed concentrations or quantities (DV) in log-log scale (C) and linear scale (D). (GIF 70 kb)

11095_2018_2379_MOESM1_ESM.tiff (542 kb)
High resolution image (TIFF 542 kb)
11095_2018_2379_Fig12_ESM.gif (139 kb)
Figure S2

Visual Predictive Checks of the PBPK model for colistin tissue data in liver (A), muscles (B), skin (C), fat (D), used for model validation. Observed data come from an independent experiment (n°5: 50,000 UI/kg of CMS divided in two IM injection per day during 3 days) that was not used for model calibration. Blue dots represent the observed tissue concentrations; highlighted with grey are the areas between the 5th and 95th percentiles of model simulations, whereas the black solid line represents the median; the purple area represents the 95% confidence interval around the median; the horizontal dashed black line represents the LOQ. In the lower panels, blue areas represent the simulation-based 95% confidence intervals for the fraction of data below the LOQ (BLOQ), whereas the blue solid line represents the actual observed fraction of BLOQ samples. (GIF 138 kb)

11095_2018_2379_MOESM2_ESM.tif (1.8 mb)
High resolution image (TIFF 1827 kb)
11095_2018_2379_Fig13_ESM.gif (95 kb)
Figure S3

Visual Predictive Checks of the PBPK model for CMS tissue data in liver (A), muscles (B), skin (C), fat (D), used for model validation. Observed data come from an independent experiment (n°5: 50,000 UI/kg of CMS divided in two IM injection per day during 3 days) that was not used for model calibration. Blue dots represent the observed tissue concentrations; highlighted with grey are the areas between the 5th and 95th percentiles of model simulations, whereas the black solid line represents the median; the purple area represents the 95% confidence interval around the median; the horizontal dashed black line represents the limit of quantification. In the lower panels, blue areas represent the simulation-based 95% confidence intervals for the fraction of data below the LOQ (BLOQ), whereas the blue solid line represents the actual observed fraction of BLOQ samples. (GIF 94 kb)

11095_2018_2379_MOESM3_ESM.tif (1.2 mb)
High resolution image (TIFF 1216 kb)
11095_2018_2379_Fig14_ESM.gif (24 kb)
Figure S4

Relative contribution of CMS and colistin in total kidney concentrations. CMS concentrations (green), colistin concentrations (red) and total concentrations in kidney after one IV of CMS (10 mg/kg) for a 50-kg pig. (GIF 23 kb)

11095_2018_2379_MOESM4_ESM.tiff (352 kb)
High resolution image (TIFF 352 kb)
11095_2018_2379_Fig15_ESM.gif (73 kb)
Figure S5

Evolution of the mass balance predicted by the model after one IV of CMS, as expressed in relative quantities for CMS (A) and colistin (B) in each compartment. GIT: gastro-intestinal tract (GIF 73 kb)

11095_2018_2379_MOESM5_ESM.tiff (544 kb)
High resolution image (TIFF 544 kb)
11095_2018_2379_Fig16_ESM.gif (80 kb)
Figure S6

Withdrawal period estimation in a 100-kg pig. Model simulation in kidney after 3 consecutive days of CMS IM injections (50,000 UI/kg of CMS divided in two injections per day) for 1000 virtual pigs of 100 kg. The grey area includes the 1st and 99th percentiles of model simulations, whereas the black solid line represents the median; the horizontal dashed black line represents the kidney MRL (0.20 μg/g). WP: withdrawal period, rounded to the next whole day (GIF 80 kb)

11095_2018_2379_MOESM6_ESM.tif (879 kb)
High resolution image (TIFF 879 kb)
11095_2018_2379_MOESM7_ESM.txt (28 kb)
ESM 1 (TXT 28 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Alexis Viel
    • 1
    • 2
    • 3
  • Jérôme Henri
    • 2
  • Salim Bouchène
    • 4
  • Julian Laroche
    • 1
    • 5
  • Jean-Guy Rolland
    • 2
  • Jacqueline Manceau
    • 2
  • Michel Laurentie
    • 2
  • William Couet
    • 1
    • 3
    • 5
  • Nicolas Grégoire
    • 1
    • 3
    Email author
  1. 1.Inserm U1070, Pôle Biologie SantéPoitiersFrance
  2. 2.Anses, Laboratoire de FougèresFougèresFrance
  3. 3.Université de Poitiers, UFR Médecine-PharmaciePoitiersFrance
  4. 4.CertaraParisFrance
  5. 5.CHU Poitiers, Laboratoire de Toxicologie-PharmacocinétiquePoitiersFrance

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