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

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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.

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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

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Authors and Affiliations

  1. Inserm U1070, Pôle Biologie Santé, Poitiers, France

    Alexis Viel, Julian Laroche, William Couet & Nicolas Grégoire

  2. Anses, Laboratoire de Fougères, Fougères, France

    Alexis Viel, Jérôme Henri, Jean-Guy Rolland, Jacqueline Manceau & Michel Laurentie

  3. Université de Poitiers, UFR Médecine-Pharmacie, Poitiers, France

    Alexis Viel, William Couet & Nicolas Grégoire

  4. Certara, Paris, France

    Salim Bouchène

  5. CHU Poitiers, Laboratoire de Toxicologie-Pharmacocinétique, Poitiers, France

    Julian Laroche & William Couet

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  1. Alexis Viel
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  2. Jérôme Henri
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  3. Salim Bouchène
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  4. Julian Laroche
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Correspondence to Nicolas Grégoire.

Electronic supplementary material

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)

High resolution image (TIFF 542 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)

High resolution image (TIFF 1827 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)

High resolution image (TIFF 1216 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)

High resolution image (TIFF 352 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)

High resolution image (TIFF 544 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)

High resolution image (TIFF 879 kb)

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Viel, A., Henri, J., Bouchène, S. et al. A Population WB-PBPK Model of Colistin and its Prodrug CMS in Pigs: Focus on the Renal Distribution and Excretion. Pharm Res 35, 92 (2018). https://doi.org/10.1007/s11095-018-2379-4

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