Pooled Population Pharmacokinetic Analysis for Exploring Ciprofloxacin Pharmacokinetic Variability in Intensive Care Patients

Tingjie Guo*, Alan Abdulla, the Dutch Antibiotic PK/PD Collaborators, Birgit C.P. Koch, Johan G.C. van Hasselt, Henrik Endeman, Jeroen A. Schouten, Roger J.M. Brüggemann, Reinier M. van Hest

*Corresponding author for this work

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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.

Original languageEnglish
Pages (from-to)869-879
Number of pages11
JournalClinical Pharmacokinetics
Volume61
Issue number6
Early online date9 Mar 2022
DOIs
Publication statusPublished - Jun 2022

Bibliographical note

Funding Information:
We thank Ronald Driessen for kindly helping us with data extraction. The Dutch Antibiotic PK/PD Collaborators: Luca F. Roggeveen, Department of Intensive Care Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. Lucas M. Fleuren, Department of Intensive Care Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. Nicole G. M. Hunfeld, Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Intensive Care, Erasmus University Medical Center, Rotterdam, The Netherlands. Tim M.J. Ewoldt, Department of Intensive Care, Erasmus University Medical Center, Rotterdam, The Netherlands. Anouk E. Muller, 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. Annemieke Dijkstra, Department of Intensive Care, Maasstad Hospital, Rotterdam, The Netherlands. Dylan W. de Lange, Department of Intensive Care and National Poisons Information Center, UMC Utrecht, Utrecht, The Netherlands. Emilie Gieling, Department of Pharmacy, Radboud UMC, Nijmegen, The Netherlands; Department of Pharmacy, UMC Utrecht, Utrecht, The Netherlands. Peter Pickkers, Department of Intensive Care, Radboud UMC, Nijmegen, The Netherlands. Jaap ten Oever, Radboud Center for Infectious Diseases, Radboud UMC, Nijmegen, The Netherlands.

Funding Information:
This work is part of the Right Dose, Right Now project by Amsterdam UMC, location Vrije Universiteit Medical Center, and OLVG Oost and the DOLPHIN project by Erasmus University Medical Center, and was partially funded by the ZonMw Rational Pharmacotherapy program (Grant ID: 848017008 and 80-83600-98-40050).

Publisher Copyright:
© 2022, The Author(s).

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