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Population pharmacokinetics of meropenem during intermittent and
continuous infusion in healthy volunteers
Rixt A. Wijma (1), Brenda C.M. de Winter (2), Birgit C.P. Koch (2), Teun van Gelder (2,3), Johan W.
Mouton (1)
(1) Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center,
Rotterdam, The Netherlands; (2) Department of Hospital Pharmacy, Erasmus University Medical
Center, Rotterdam, The Netherlands; (3) Department of Internal Medicine, Erasmus University
Medical Center, Rotterdam, The Netherlands.
Objectives:
Meropenem is a broad-spectrum antibacterial agent that has been used for decades.
In an era of increasing emergence of drug resistance and lack of new antibiotics, old off-patent
antibiotics are increasingly being prescribed to patients. However, many of these were developed in
an age before the advent of a structured process for drug assessment and approval. As part of a
large, European project, this study was conducted to describe the population pharmacokinetics of
intravenous meropenem to optimize plasma levels related to MICs.
Methods:
Eight healthy volunteers received meropenem on 2 separate occasions either
intermittently (3 doses, 10 mg/kg every 6 hours, infusion time 25 minutes) or by continuous
administration (30 mg/kg meropenem over 18h with a loading dose of 0.2 mg/kg). Venous blood
samples during the intermittent regime were taken before the third dose and at: 10, 20, 30, 40, 50,
60 min and 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10 and 12 h after the start of the third infusion. Blood samples
during the continuous regime were taken before the loading dose and at: 10, 20, 30, 40, 50, 60 min
and 1.5, 2, 4, 8, 12, 14, 16, 18, 19, 20, 22, 24 and 26 h after the start of the infusion. . The data were
analysed with nonlinear mixed effect modelling (NONMEM, version 7.2.0) [1]. One-, two- and threecompartments were evaluated in combination with different covariates. Model selection criteria
were decrease in objective function, diagnostic plots and visual predictive checks.
Results:
A two-compartment model fitted the data best with volume of distribution and
clearance as relevant covariates. Clearance and volume of the central compartment were 19.3 ± 0.6
L/h and 13.1 ± 0.8 L, respectively. Forward inclusion and backward elimination was used to test
significant improvement of the model by the covariates. Neither age, weight, nor creatinine
clearance was found to be significant. No between occasions variability was found.
Conclusions: The pharmacokinetics of meropenem is best described by a two-compartment model
with no covariates. Our results show that the pharmacokinetics of meropenem are stable in this
population. This is not comparable with earlier research were body weight and creatinine clearance
were found to be significant covariates [2,3]. This can be explained by the fact that these studies
were conducted in patients with different pharmacokinetic properties.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon
Development Solutions, Ellicott City, Maryland, USA.
[2] Chonghua Li, Joseph L. Kuti, Charles H. Nightingale et al. Population Pharmacokinetic Analysis and
Dosing Regimen Optimization of Meropenem in Adult Patients. Journal of Clinical Pharmacology,
2006; 46:1171-1178.
[3] Amelia Ramon-Lopez, Jane M. Allen, Alison H. Thomson, et al. Dosing regimen of meropenem for
adults with severe burns: a population pharmacokinetic study with Monte Carlo simulations. J
Antimicrob Chemother 2015; 70: 882–890.