Population Pharmacokinetics of Unbound and Total Teicoplanin in Critically Ill Pediatric Patients
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ORIGINAL RESEARCH ARTICLE
Population Pharmacokinetics of Unbound and Total Teicoplanin in Critically Ill Pediatric Patients L. B. S. Aulin1 · P. De Paepe2 · E. Dhont3 · A. de Jaeger3 · J. Vande Walle4 · W. Vandenberghe3 · B. C. McWhinney5 · J. P. J. Ungerer5,6 · J. G. C. van Hasselt1 · P. A. J. G. De Cock2,3,7 Accepted: 16 September 2020 © Springer Nature Switzerland AG 2020
Abstract Background and Objectives Teicoplanin is a highly protein-bound antibiotic, increasingly used to treat serious Gram-positive infections in critically ill children. Maturational and pathophysiological intensive care unit-related changes often lead to altered pharmacokinetics. In this study, the objectives were to develop a pediatric population-pharmacokinetic model of unbound and total teicoplanin concentrations, to investigate the impact of plasma albumin levels and renal function on teicoplanin pharmacokinetics, and to evaluate the efficacy of the current weight-based dosing regimen. Methods An observational pharmacokinetic study was performed and blood samples were collected for quantification of unbound and total concentrations of teicoplanin after the first dose and in assumed steady-state conditions. A populationpharmacokinetic analysis was conducted using a standard sequential approach and Monte Carlo simulations were performed for a probability of target attainment analysis using previously published pharmacokinetic–pharmacodynamic targets. Results A two-compartment model with allometric scaling of pharmacokinetic parameters and non-linear plasma protein binding best described the data. Neither the inclusion of albumin nor the renal function significantly improved the model and no other covariates were supported for inclusion in the final model. The probability of target attainment analysis showed that the standard dosing regimen does not satisfactory attain the majority of the proposed targets. Conclusions We successfully characterized the pharmacokinetics of unbound and total teicoplanin in critically ill pediatric patients. The highly variable unbound fraction of teicoplanin could not be predicted using albumin levels, which may support the use of therapeutic drug monitoring of unbound concentrations. Poor target attainment was shown for the most commonly used dosing regimen, regardless of the pharmacokinetic–pharmacodynamic target evaluated.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40262-020-00945-4) contains supplementary material, which is available to authorized users. * P. A. J. G. De Cock [email protected] 1
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Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium
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Department of Pediatric Nephrology, Ghent University Hospital, Ghent, Belgium
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Department of Chemical Pathology, Pathology Queensland, Brisbane, QL
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