Population pharmacokinetics of imipenem in critically ill patients with suspected ventilator-associated pneumonia and evaluation of dosage regimens.

Abstract : OBJECTIVES: Significant alterations in the pharmacokinetics (PK) of antimicrobials have been reported in critically ill patients. We describe PK parameters of imipenem in intensive care unit (ICU) patients with suspected ventilator-associated pneumonia (VAP) and evaluate several dosage regimens. METHODS: This French multicentre, prospective, open-label study was conducted in ICU patients with a presumptive diagnosis of Gram-negative bacilli VAP who empirically received imipenem I.V. q8h. Plasma imipenem concentrations were measured during the 4(th) imipenem infusion using 6 samples (trough, 0.5, 1, 2, 5 and 8 hours). Data were analysed with a population approach using the SAEM algorithm in Monolix 4.2. A Monte Carlo simulation was performed to evaluate six dosage regimens: 500, 750 or 1000mg with administration q6h or q8h. The pharmacodynamic target was defined as the probability of achieving a fractional time (fT) above minimum inhibitory concentration (MIC) greater than 40%. RESULTS: Fifty-one patients were included in the PK analysis. Imipenem concentration data were best described by a two-compartment model with three covariates (creatinine clearance, total body weight and serum albumin). Estimated clearance (between-subject variability) was 13.2 L/h (38%), and estimated central volume 20.4 L (31%). At an MIC of 4 μg/mL, the probability of achieving 40% fT >MIC was 91.8%, for 0.5-h infusions of 750mg q6h, 86.0% of 1000mg q8h and 96.9% of 1000mg q6h. CONCLUSION: This population PK model accurately estimated imipenem concentrations in ICU patients. The simulation showed that for these patients the best dosage regimen of imipenem is 750mg q6h and not 1000mg q8h.
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British Journal of Clinical Pharmacology, Wiley, 2014, 78 (5), pp.1022-34. 〈10.1111/bcp.12435〉
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Camille Couffignal, Olivier Pajot, Cédric Laouénan, Charles Burdet, Arnaud Foucrier, et al.. Population pharmacokinetics of imipenem in critically ill patients with suspected ventilator-associated pneumonia and evaluation of dosage regimens.. British Journal of Clinical Pharmacology, Wiley, 2014, 78 (5), pp.1022-34. 〈10.1111/bcp.12435〉. 〈inserm-01006424〉

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