Mechanism-based pharmacokinetic/pharmacodynamic modeling of aerosolized colistin in a mouse lung infection model

Yu-Wei Lin, Qi Tony Zhou, Mei-Ling Han, Nikolas J. Onufrak, Ke Chen, Jiping Wang, Alan Forrest, Hak-Kim Chan, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

Optimized dosage regimens of aerosolized colistin (as colistin methanesulfonate [CMS]) are urgently required to maximize bacterial killing against multidrug-resistant Gram-negative bacteria while minimizing toxicity. This study aimed to develop a mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model (MBM) for aerosolized colistin based upon PK/PD data in neutropenic infected mice and to perform a deterministic simulation with the PK of aerosolized colistin (as CMS) in critically ill patients. In vivo time-kill experiments were carried out with three different strains of Pseudomonas aeruginosa. An MBM was developed in S-ADAPT and evaluated by assessing its ability to predict the PK/PD index associated with efficacy in mice. A deterministic simulation with human PK data was undertaken to predict the efficacy of current dosage regimens of aerosolized colistin in critically ill patients. In the final MBM, the total bacterial population for each isolate consisted of colistin-susceptible and -resistant subpopulations. The antimicrobial efficacy of aerosolized colistin was best described by a sigmoidal Emax model whereby colistin enhanced the rate of bacterial death. Deterministic simulation with human PK data predicted that an inhalational dosage regimen of 60 mg colistin base activity (CBA) every 12 h is needed to achieve a 2-log10 bacterial reduction (as the number of CFU per lung) in critically ill patients at 24 h after commencement of inhaled therapy. In conclusion, the developed MBM is a useful tool for optimizing inhalational dosage regimens of colistin. Clinical studies are warranted to validate and refine our MBM for aerosolized colistin.

Original languageEnglish
Article numbere01965-17
Number of pages14
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018

Keywords

  • Mechanism-based modeling
  • Multidrug-resistant Gram-negative bacteria
  • Polymyxin
  • Population pharmacokinetics and pharmacodynamics
  • Pseudomonas aeruginosa
  • Pulmonary administration
  • Respiratory tract infections

Cite this

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title = "Mechanism-based pharmacokinetic/pharmacodynamic modeling of aerosolized colistin in a mouse lung infection model",
abstract = "Optimized dosage regimens of aerosolized colistin (as colistin methanesulfonate [CMS]) are urgently required to maximize bacterial killing against multidrug-resistant Gram-negative bacteria while minimizing toxicity. This study aimed to develop a mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model (MBM) for aerosolized colistin based upon PK/PD data in neutropenic infected mice and to perform a deterministic simulation with the PK of aerosolized colistin (as CMS) in critically ill patients. In vivo time-kill experiments were carried out with three different strains of Pseudomonas aeruginosa. An MBM was developed in S-ADAPT and evaluated by assessing its ability to predict the PK/PD index associated with efficacy in mice. A deterministic simulation with human PK data was undertaken to predict the efficacy of current dosage regimens of aerosolized colistin in critically ill patients. In the final MBM, the total bacterial population for each isolate consisted of colistin-susceptible and -resistant subpopulations. The antimicrobial efficacy of aerosolized colistin was best described by a sigmoidal Emax model whereby colistin enhanced the rate of bacterial death. Deterministic simulation with human PK data predicted that an inhalational dosage regimen of 60 mg colistin base activity (CBA) every 12 h is needed to achieve a 2-log10 bacterial reduction (as the number of CFU per lung) in critically ill patients at 24 h after commencement of inhaled therapy. In conclusion, the developed MBM is a useful tool for optimizing inhalational dosage regimens of colistin. Clinical studies are warranted to validate and refine our MBM for aerosolized colistin.",
keywords = "Mechanism-based modeling, Multidrug-resistant Gram-negative bacteria, Polymyxin, Population pharmacokinetics and pharmacodynamics, Pseudomonas aeruginosa, Pulmonary administration, Respiratory tract infections",
author = "Yu-Wei Lin and Zhou, {Qi Tony} and Mei-Ling Han and Onufrak, {Nikolas J.} and Ke Chen and Jiping Wang and Alan Forrest and Hak-Kim Chan and Jian Li",
year = "2018",
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day = "1",
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language = "English",
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Mechanism-based pharmacokinetic/pharmacodynamic modeling of aerosolized colistin in a mouse lung infection model. / Lin, Yu-Wei; Zhou, Qi Tony; Han, Mei-Ling; Onufrak, Nikolas J.; Chen, Ke; Wang, Jiping; Forrest, Alan; Chan, Hak-Kim; Li, Jian.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 3, e01965-17, 01.03.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Mechanism-based pharmacokinetic/pharmacodynamic modeling of aerosolized colistin in a mouse lung infection model

AU - Lin, Yu-Wei

AU - Zhou, Qi Tony

AU - Han, Mei-Ling

AU - Onufrak, Nikolas J.

AU - Chen, Ke

AU - Wang, Jiping

AU - Forrest, Alan

AU - Chan, Hak-Kim

AU - Li, Jian

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N2 - Optimized dosage regimens of aerosolized colistin (as colistin methanesulfonate [CMS]) are urgently required to maximize bacterial killing against multidrug-resistant Gram-negative bacteria while minimizing toxicity. This study aimed to develop a mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model (MBM) for aerosolized colistin based upon PK/PD data in neutropenic infected mice and to perform a deterministic simulation with the PK of aerosolized colistin (as CMS) in critically ill patients. In vivo time-kill experiments were carried out with three different strains of Pseudomonas aeruginosa. An MBM was developed in S-ADAPT and evaluated by assessing its ability to predict the PK/PD index associated with efficacy in mice. A deterministic simulation with human PK data was undertaken to predict the efficacy of current dosage regimens of aerosolized colistin in critically ill patients. In the final MBM, the total bacterial population for each isolate consisted of colistin-susceptible and -resistant subpopulations. The antimicrobial efficacy of aerosolized colistin was best described by a sigmoidal Emax model whereby colistin enhanced the rate of bacterial death. Deterministic simulation with human PK data predicted that an inhalational dosage regimen of 60 mg colistin base activity (CBA) every 12 h is needed to achieve a 2-log10 bacterial reduction (as the number of CFU per lung) in critically ill patients at 24 h after commencement of inhaled therapy. In conclusion, the developed MBM is a useful tool for optimizing inhalational dosage regimens of colistin. Clinical studies are warranted to validate and refine our MBM for aerosolized colistin.

AB - Optimized dosage regimens of aerosolized colistin (as colistin methanesulfonate [CMS]) are urgently required to maximize bacterial killing against multidrug-resistant Gram-negative bacteria while minimizing toxicity. This study aimed to develop a mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model (MBM) for aerosolized colistin based upon PK/PD data in neutropenic infected mice and to perform a deterministic simulation with the PK of aerosolized colistin (as CMS) in critically ill patients. In vivo time-kill experiments were carried out with three different strains of Pseudomonas aeruginosa. An MBM was developed in S-ADAPT and evaluated by assessing its ability to predict the PK/PD index associated with efficacy in mice. A deterministic simulation with human PK data was undertaken to predict the efficacy of current dosage regimens of aerosolized colistin in critically ill patients. In the final MBM, the total bacterial population for each isolate consisted of colistin-susceptible and -resistant subpopulations. The antimicrobial efficacy of aerosolized colistin was best described by a sigmoidal Emax model whereby colistin enhanced the rate of bacterial death. Deterministic simulation with human PK data predicted that an inhalational dosage regimen of 60 mg colistin base activity (CBA) every 12 h is needed to achieve a 2-log10 bacterial reduction (as the number of CFU per lung) in critically ill patients at 24 h after commencement of inhaled therapy. In conclusion, the developed MBM is a useful tool for optimizing inhalational dosage regimens of colistin. Clinical studies are warranted to validate and refine our MBM for aerosolized colistin.

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KW - Polymyxin

KW - Population pharmacokinetics and pharmacodynamics

KW - Pseudomonas aeruginosa

KW - Pulmonary administration

KW - Respiratory tract infections

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