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 Grégoire
Research Paper
  • 155 Downloads

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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 

Abbreviations

ADME

Absorption, distribution, metabolism, excretion

BLOQ

Below the limit of quantification

BW

Body weight

CBA

Colistin base activity

CMS

Colistimethate sodium

DV

Observed value

fu

Unbound fraction

GFR

Glomerular filtration rate

GIT

Gastro-intestinal tract

HPLC-MS/MS

High-performance liquid chromatography coupled with tandem mass spectrometry

IIV

Interindividual variability

IM

Intramuscular

IPRED

Individual prediction

IV

Intravenous

LOQ

Limit of quantification

MRL

Maximal residue limits

NLME

Nonlinear mixed effects

OFV

Objective function value

PBPK

Physiologically-based pharmacokinetic

PK

Pharmacokinetics

PRED

Population prediction

RV

Residual variability

SIR

Sampling importance resampling

t1/2

Half-life

VPC

Visual predictive checks

WB-PBPK

Whole body physiologically-based pharmacokinetic

WP

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
  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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