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A population pharmacokinetic model for cefuroxime using cystatin C as a marker of renal function
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (Farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
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2006 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 62, no 3, 297-303 p.Article in journal (Refereed) Published
Abstract [en]

Aims: Since cefuroxime mainly is excreted by renal filtration, dosing is currently based on serum creatinine (Scr) or creatinine clearance (CLcr). However, it has been suggested that cystatin C (CysC) is superior to Scr as a marker of renal function. The aim of this prospective study was to develop a population model that describes the pharmacokinetics of cefuroxime and to investigate the usefulness of CysC as a covariate of the model parameters.

Methods: Ninety-seven patients were studied (CLcr range 6.5-115 ml min(-1)). Blood samples (n = 407) for the determination of cefuroxime were withdrawn according to a sparse data sampling schedule and analysed by liquid chromatography mass spectrometry. The population analysis was performed in NONMEM.

Results: A two-compartment model described the data well. The biomarkers Scr, CLcr and CysC were evaluated as covariates on clearance (CL). The model that included CysC generated the best fit. In the final population model CL was a function of CysC and body weight, whereas V-1 was only a function of body weight. Final parameter estimates (relative standard errors) were 6.00 (3.2%) l h(-1), 11.4 (5.3%) l and 5.11 (11%) l for CL, V-1 and V-2, respectively.

Conclusion: Based on the results of the present study, and because CysC is practical to use in the clinic, it is suggested that individual dosing of cefuroxime may be based on CysC rather than on Scr or CLcr. Furthermore, our final population model may be useful as a tool when designing new dosing schedules for cefuroxime.

Place, publisher, year, edition, pages
2006. Vol. 62, no 3, 297-303 p.
Keyword [en]
cefuroxime, cystatin C, NONMEM, pharmacokinetics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94166DOI: 10.1111/j.1365-2125.2006.02652.xISI: 000239694000007PubMedID: 16934045OAI: oai:DiVA.org:uu-94166DiVA: diva2:167922
Available from: 2006-03-31 Created: 2006-03-31 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Using Pharmacokinetic and Pharmacodynamic Principles to Evaluate Individualisation of Antibiotic Dosing – Emphasis on Cefuroxime
Open this publication in new window or tab >>Using Pharmacokinetic and Pharmacodynamic Principles to Evaluate Individualisation of Antibiotic Dosing – Emphasis on Cefuroxime
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cefuroxime is a renally eliminated antibiotic used against a variety of different bacterial infections. The pharmacokinetics (PK) for cefuroxime was studied in 97 hospitalized patients using population analysis. To be able to measure cefuroxime in human serum a new sensitive analytical method was developed using mass spectrometry detection. The method was validated and shown to be sensitive and selective. Cystatin C was found to be a better covariate for cefuroxime clearance compared to the traditionally used creatinine clearance (CLcr). This relation might be useful when designing dosing strategies for cefuroxime and other renally eliminated drugs.

The time-courses of the biomarkers C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6) and body temperature were studied for the first 72 hours of cefuroxime treatment and was related to the duration of illness previous treatment with cefuroxime and to time to step-down of treatment. When duration of illness was short, CRP and SAA were showed increasing levels. None of the biomarkers could be used to differentiate between early or late step-down of therapy.

By use of known PK and pharmacodynamic (PD) principles, dosing strategies based on CLcr for cefuroxime were estimated using minimization of a risk function. The risk function was constructed with the aim to expose patients to cefuroxime concentration above minimum inhibitory concentration (MIC) for 50 % of the dosing interval and to minimize the amount of drug administered in excess to reach the aim. Based on evaluation using wild type MIC distributions for Escherichia coli and Streptococcus pneumoniae improved dosing strategies were selected.

In vitro experiments were performed exposing Streptococcus pyogenes to constant concentration of benzylpenicillin, cefuroxime, erythromycin, moxifloxacin or vancomycin. A semi-mechanistic PK/PD model characterizing the time-course of the antibacterial effect was developed using all data simultaneously. Internal validation showed the model being predictive and robust.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 29
Keyword
Pharmacokinetics/Pharmacotherapy, Cefuroxime, pharmacokinetics, pharmacodynamics, dosing individualisation, NONMEM, Farmakokinetik/Farmakoterapi
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-6639 (URN)91-554-6499-8 (ISBN)
Public defence
2006-04-21, B22, BMC, Uppsala, 09:15
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Supervisors
Available from: 2006-03-31 Created: 2006-03-31 Last updated: 2011-06-27Bibliographically approved

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Lannergård, AndersLarsson, AndersCars, OttoKarlsson, Mats O.

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