Population pharmacokinetics of ceftriaxone and pharmacodynamic considerations in haemodialysed patients

To determine the pharmacokinetic parameters of ceftriaxone following an infusion in haemodialysed outpatients and to use these parameters for an optimisation of dosing based on pharmacodynamic indices. Fifty haemodialysed patients were enrolled in a single-centre, prospective, open-label study. They...

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Bibliographic Details
Published in:Clinical pharmacokinetics 2006-01, Vol.45 (5), p.493-501
Main Authors: SIMON, Nicolas, DUSSOL, Bertrand, SAMPOL, Emmanuelle, PURGUS, Raj, BRUNET, Philippe, LACARELLE, Bruno, BERLAND, Yvon, BRUGUEROLLE, Bernard, URIEN, Saik
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Anti-Bacterial Agents - blood
Anti-Bacterial Agents - pharmacokinetics
Anti-Bacterial Agents - therapeutic use
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Biological and medical sciences
Bronchopneumonia - drug therapy
Bronchopneumonia - metabolism
Ceftriaxone - blood
Ceftriaxone - pharmacokinetics
Ceftriaxone - therapeutic use
Emergency and intensive care: renal failure. Dialysis management
Female
Humans
Intensive care medicine
Kidney Failure, Chronic - drug therapy
Kidney Failure, Chronic - metabolism
Male
Medical sciences
Middle Aged
Pharmacology. Drug treatments
Renal Dialysis
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Summary:To determine the pharmacokinetic parameters of ceftriaxone following an infusion in haemodialysed outpatients and to use these parameters for an optimisation of dosing based on pharmacodynamic indices. Fifty haemodialysed patients were enrolled in a single-centre, prospective, open-label study. They received short intravenous infusions of ceftriaxone 1 or 2 g every 48 hours for bronchopneumonia immediately after the dialysis session. Total plasma concentrations of ceftriaxone were analysed with a population pharmacokinetic approach using nonlinear mixed-effects modelling. Free drug concentrations were derived from published binding parameters in order to estimate the time when they exceed the minimum inhibitory concentration (MIC). The pharmacokinetics were best described by a two-compartment model. None of the covariates tested (age, bodyweight, height, sex, body mass index, albumin) influenced the pharmacokinetic parameters. The estimated population pharmacokinetic parameters (interindividual variability [percentage of coefficient of variation]) were clearance 0.36 L/h (48%), volume of distribution of the central compartment 4.53 L (47%), intercompartmental clearance 10.8 L/h and volume of distribution of the peripheral compartment 9.54 L (63%). The terminal elimination half-life (t(1/2)beta) from plasma was 27.5 hours. The mean (range) times when the free drug concentration exceeded the MIC (T>MIC) following ceftriaxone 1 g infusion were 60.3 (53.0-67.7) hours and 2.5 (1.0-3.9) hours for the breakpoints 1 and 8 mg/L (based on free drug concentration), respectively. After administration of ceftriaxone 2 g, the T>MIC was 88.5 (78.8-98.3) hours and 17.7 (13.3-22.0) hours for the breakpoints 1 and 8 mg/L, respectively. The simulated free drug concentrations (median, first and third quartile) for 48 and 72 hours following the first dose of ceftriaxone 1g were 1.11, 0.63 and 1.89 mg/L, and 0.63, 0.28 and 1.18 mg/L, respectively. For ceftriaxone 2g infusion, the simulated free concentrations (median, first and third quartile) at 48 and 72 hours were 2.50, 1.40 and 4.52 mg/L, and 1.37, 0.60 and 2.70 mg/L, respectively. On the basis of decreased clearance in haemodialysed patients, it can be argued that the dose of ceftriaxone should be decreased or the delay between doses should be increased. However, taking into account pharmacodynamic considerations, this study showed that following intravenous administration of ceftriaxone 1 g after each dialysis session, so
ISSN:0312-5963
1179-1926
DOI:10.2165/00003088-200645050-00004