Pooled Population Pharmacokinetic Analysis for Exploring Ciprofloxacin Pharmacokinetic Variability in Intensive Care Patients
Clinical Pharmacokinetics, vol. 61, pp. 869–879
Abstract
BACKGROUND AND OBJECTIVE: Previous pharmacokinetic (PK) studies of ciprofloxacin in intensive care (ICU) patients have shown large differences in estimated PK parameters, suggesting that further investigation is needed for this population. Hence, we performed a pooled population PK analysis of ciprofloxacin after intravenous administration using individual patient data from three studies. Additionally, we studied the PK differences between these studies through a post-hoc analysis. METHODS: Individual patient data from three studies (study 1, 2, and 3) were pooled. The pooled data set consisted of 1094 ciprofloxacin concentration-time data points from 140 ICU patients. Nonlinear mixed-effects modeling was used to develop a population PK model. Covariates were selected following a stepwise covariate modeling procedure. To analyze PK differences between the three original studies, random samples were drawn from the posterior distribution of individual PK parameters. These samples were used for a simulation study comparing PK exposure and the percentage of target attainment between patients of these studies. RESULTS: A two-compartment model with first-order elimination best described the data. Inter-individual variability was added to the clearance, central volume, and peripheral volume. Inter-occasion variability was added to clearance only. Body weight was added to all parameters allometrically. Estimated glomerular filtration rate on ciprofloxacin clearance was identified as the only covariate relationship resulting in a drop in inter-individual variability of clearance from 58.7 to 47.2%. In the post-hoc analysis, clearance showed the highest deviation between the three studies with a coefficient of variation of 14.3% for posterior mean and 24.1% for posterior inter-individual variability. The simulation study showed that following the same dose regimen of 400 mg three times daily, the area under the concentration-time curve of study 3 was the highest with a mean area under the concentration-time curve at 24 h of 58 mg·h/L compared with that of 47.7 mg·h/L for study 1 and 47.6 mg·h/L for study 2. Similar differences were also observed in the percentage of target attainment, defined as the ratio of area under the concentration-time curve at 24 h and the minimum inhibitory concentration. At the epidemiological cut-off minimum inhibitory concentration of Pseudomonas aeruginosa of 0.5 mg/L, percentage of target attainment was only 21%, 18%, and 38% for study 1, 2, and 3, respectively. CONCLUSIONS: We developed a population PK model of ciprofloxacin in ICU patients using pooled data of individual patients from three studies. A simple ciprofloxacin dose recommendation for the entire ICU population remains challenging owing to the PK differences within ICU patients, hence dose individualization may be needed for the optimization of ciprofloxacin treatment.
Authors 19
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Tingjie Guo corresponding Aachen Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands. t.guo@lacdr.leidenuniv.nl
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
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Affiliation as printed
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
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Affiliation as printed
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
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J. G. Coen van Hasselt Aachen Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research
Affiliation as printed
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
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Affiliation as printed
Department of Intensive Care, Erasmus University Medical Center, Rotterdam, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Intensive Care, Radboudumc-CWZ Center of Expertise for Mycology, Radboud UMC, Nijmegen, The Netherlands
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Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Intensive Care Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Health Sciences
Affiliation as printed
Department of Pharmacy, Radboud Center for Infectious Diseases, Radboud Institute for Health Sciences, Radboud UMC, Nijmegen, The Netherlands
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Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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Erasmus MC · Medisch Centrum Haaglanden · Amsterdam University Medical Centers · Stichting Haaglanden Medisch Centrum · Vrije Universiteit Amsterdam · Erasmus University Rotterdam
Affiliation as printed
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Intensive Care,
Department of Intensive Care , Erasmus University Medical Center, Rotterdam, The Netherlands
Department of Intensive Care Medicine, Amsterdam UMC, Vrije Uni-versiteit Amsterdam, Amsterdam, The Netherlands
Department of Intensive Care,
Department of Intensive Care, Erasmus Univer-sity Medical Center, Rotterdam, The Netherlands
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Medical Microbiology, Haaglanden Medical Center, The Hague, The Netherlands
Erasmus University Medical Center, Rotterdam, The Netherlands
versiteit Amsterdam, Amsterdam, The Netherlands
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Erasmus MC · Medisch Centrum Haaglanden · Amsterdam University Medical Centers · Stichting Haaglanden Medisch Centrum · Vrije Universiteit Amsterdam · Erasmus University Rotterdam
Affiliation as printed
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Intensive Care,
Department of Intensive Care , Erasmus University Medical Center, Rotterdam, The Netherlands
Department of Intensive Care Medicine, Amsterdam UMC, Vrije Uni-versiteit Amsterdam, Amsterdam, The Netherlands
Department of Intensive Care,
Department of Intensive Care, Erasmus Univer-sity Medical Center, Rotterdam, The Netherlands
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Medical Microbiology, Haaglanden Medical Center, The Hague, The Netherlands
Erasmus University Medical Center, Rotterdam, The Netherlands
versiteit Amsterdam, Amsterdam, The Netherlands
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Erasmus MC · Medisch Centrum Haaglanden · Amsterdam University Medical Centers · Stichting Haaglanden Medisch Centrum · Vrije Universiteit Amsterdam · Erasmus University Rotterdam
Affiliation as printed
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Intensive Care,
Department of Intensive Care , Erasmus University Medical Center, Rotterdam, The Netherlands
Department of Intensive Care Medicine, Amsterdam UMC, Vrije Uni-versiteit Amsterdam, Amsterdam, The Netherlands
Department of Intensive Care,
Department of Intensive Care, Erasmus Univer-sity Medical Center, Rotterdam, The Netherlands
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Medical Microbiology, Haaglanden Medical Center, The Hague, The Netherlands
Erasmus University Medical Center, Rotterdam, The Netherlands
versiteit Amsterdam, Amsterdam, The Netherlands
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Erasmus MC · Medisch Centrum Haaglanden · Amsterdam University Medical Centers · Stichting Haaglanden Medisch Centrum · Vrije Universiteit Amsterdam · Erasmus University Rotterdam
Affiliation as printed
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Intensive Care,
Department of Intensive Care , Erasmus University Medical Center, Rotterdam, The Netherlands
Department of Intensive Care Medicine, Amsterdam UMC, Vrije Uni-versiteit Amsterdam, Amsterdam, The Netherlands
Department of Intensive Care,
Department of Intensive Care, Erasmus Univer-sity Medical Center, Rotterdam, The Netherlands
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Medical Microbiology, Haaglanden Medical Center, The Hague, The Netherlands
Erasmus University Medical Center, Rotterdam, The Netherlands
versiteit Amsterdam, Amsterdam, The Netherlands
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Erasmus MC · Medisch Centrum Haaglanden · Amsterdam University Medical Centers · Stichting Haaglanden Medisch Centrum · Vrije Universiteit Amsterdam · Erasmus University Rotterdam
Affiliation as printed
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Intensive Care,
Department of Intensive Care , Erasmus University Medical Center, Rotterdam, The Netherlands
Department of Intensive Care Medicine, Amsterdam UMC, Vrije Uni-versiteit Amsterdam, Amsterdam, The Netherlands
Department of Intensive Care,
Department of Intensive Care, Erasmus Univer-sity Medical Center, Rotterdam, The Netherlands
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Medical Microbiology, Haaglanden Medical Center, The Hague, The Netherlands
Erasmus University Medical Center, Rotterdam, The Netherlands
versiteit Amsterdam, Amsterdam, The Netherlands
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