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Pharmaceutical Research

, Volume 32, Issue 10, pp 3403–3414 | Cite as

Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS Nebulisation in Baboon Monkeys

  • Sandrine MarchandEmail author
  • Salim Bouchene
  • Michèle de Monte
  • Laurent Guilleminault
  • Jérôme Montharu
  • Maria Cabrera
  • Nicolas Grégoire
  • Patrice Gobin
  • Patrice Diot
  • William Couet
  • Laurent Vecellio
Research Paper

Abstract

Purpose

The objective of this study was to compare two different nebulizers: Eflow rapid® and Pari LC star® by scintigraphy and PK modeling to simulate epithelial lining fluid concentrations from measured plasma concentrations, after nebulization of CMS in baboons.

Methods

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.

Results

Higher aerosol distribution into lungs was observed by scintigraphy, when CMS was nebulized with Pari LC® star than with Eflow Rapid® 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 star® than the Eflow rapid® system.

Conclusions

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 Star® than with the Eflow Rapid® system.

KEY WORDS

colistin nebulization pharmacokinetic modelling scintigraphy 

Abbreviations

99m Tc-DTPA

99m technetium-diethylene triamino pentaacetic acid

AUCELF

Area under the ELF concentrations-time curve

BAL

Broncho-alveolar lavage

C

Central lung

CBA

Colistin base activity

CF

Cystic fibrosis

CMS

Colistin methansulphonate

ELF

Epithelial lining fluid

ET

Extrathoracic

GDS

Geometric standard deviation

HPLC

High-performance liquid chromatography

IIV

Inter-individual variability

IM

Intramuscular

IOV

Inter-occasion variability

IV

Intravenous

LC-MS/MS

Liquid chromatography coupled with tandem mass spectrometry

LLOQ

Lower limit of quantification

MMAD

Mass median aerodynamic diameter

NLME

Non-linear mixed effects

OFV

Objective function value

P

Peripheral lung

PK

Pharmacokinetics

ROIs

Regions of interest

SC

Subcutaneous

T

Lung

TH

Thoracic

VAP

Ventilator-associated pneumonia

VPC

Visual predictive checks

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

The authors thank Georges Roseau for its technical assistance in this study.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Sandrine Marchand
    • 1
    • 2
    • 3
    Email author
  • Salim Bouchene
    • 4
  • Michèle de Monte
    • 5
  • Laurent Guilleminault
    • 5
  • Jérôme Montharu
    • 5
  • Maria Cabrera
    • 5
  • Nicolas Grégoire
    • 1
    • 2
  • Patrice Gobin
    • 1
    • 3
  • Patrice Diot
    • 5
  • William Couet
    • 1
    • 2
    • 3
  • Laurent Vecellio
    • 5
  1. 1.INSERM U-1070, Pôle Biologie SantéPoitiers Cedex 9France
  2. 2.Faculté de Médecine et de PharmacieUniversité de PoitiersPoitiers Cedex 9France
  3. 3.Laboratoire de Toxicologie et de PharmacocinétiqueCHU de PoitiersPoitiersFrance
  4. 4.Faculty of Pharmacy, Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden
  5. 5.Centre d’Etude des Pathologies Respiratoires, INSERM UMR 1100/EA6305Université de Tours, Faculté de MédecineToursFrance

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