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

Abstract

Aims: 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 and evaluate several dosage regimens.

Methods: This French multicentre, prospective, open-label study was conducted in ICU patients with a presumptive diagnosis of ventilator-associated pneumonia caused by Gram-negative bacilli, who empirically received imipenem intravenously every 8 h. Plasma imipenem concentrations were measured during the fourth imipenem infusion using six samples (trough, 0.5, 1, 2, 5 and 8 h). Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm in Monolix 4.2. A Monte Carlo simulation was performed to evaluate the following six dosage regimens: 500, 750 or 1000 mg with administration every 6 or 8 h. The pharmacodynamic target was defined as the probability of achieving a fractional time above the minimal inhibitory concentration (MIC) of >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 bodyweight and serum albumin). Estimated clearance (between-subject variability) was 13.2 l h(-1) (38%) and estimated central volume 20.4 l (31%). At an MIC of 4 μg ml(-1) , the probability of achieving 40% fractional time > MIC was 91.8% for 0.5 h infusions of 750 mg every 6 h, 86.0% for 1000 mg every 8 h and 96.9% for 1000 mg every 6 h.

Conclusions: 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 750 mg every 6 h and not 1000 mg every 8 h.

Trial registration: ClinicalTrials.gov NCT00950222.

Keywords: critical care; imipenem; population pharmacokinetics; ventilator-associated pneumonia.

Figure 1

Spaghetti plot of imipenem concentrations vs. time following four doses for the 51 intensive care unit patients included in the analysis. Data above the limit of quantification are presented as open blues circles, data below the limit of quantification (BQL) as open red circles at the limit of quantification

Figure 2

Relationship between estimated individual pharmacokinetic parameters and covariates. (A) Clearance vs. 4 h creatinine clearance. (B) Central volume vs. total bodyweight. (C) Central volume vs. serum albumin. In each panel, model predictions are displayed as the red curve

Figure 3

Goodness-of-fit plots for the final model with covariates: observations (A) and population weighted residuals (PWRES; B) vs. population predicted values; and observations (C) and individual weighted residuals (IWRES; D) vs. individual predicted values. Observations are plotted as blue circles and BQL data as red circles. Locally weighted scatterplot smoothed curves are plotted as blue curves

Figure 4

Visual predictive check (A) and normalized prediction distribution error (NPDE; B) vs. time since first dose for the final model. Visual predictive check details are as follows: the continuous green lines indicate the 10th, 50th and 90th percentiles for observed data; the shaded blue and pink areas represent 90% prediction intervals from the corresponding percentiles calculated from simulated data. Observations are plotted as blue circles and BQL data as red circles

Figure 5

Simulated probabilities of pharmacodynamic target attainment vs. minimal inhibitory concentration (MIC) for various imipenem current dosage regimens at steady state: 40% fractional time (fT) > MIC (A) and 100% fT > MIC (B). Vertical dotted lines are displayed for MIC = 2 μg ml⁻¹ and MIC = 4 μg ml⁻¹, which are the thresholds currently observed for Gram-negative bacteria in the intensive care unit. , 500 mg every 8 h (q8h); , 500 mg every 6 h (q6h); , 750 mg q8h; , 750 mg q6h; , 1000 mg q8h; , 1000 mg q6h

Figure 6

Predicted concentrations of imipenem for median value of parameters for 1000 mg q8h () or 1000 mg q6h () or 750 mg q6h ()