Population pharmacokinetics and target attainment of ciprofloxacin in critically ill patients

Abstract

Purpose: To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens.

Methods: Non-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an ƒAUC_0-24/MIC ≥ 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens.

Results: A total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400-1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m², and eGFR of 58.5 mL/min/1.73 m². The median ƒAUC_0-24 and ƒC_max were 29.9 mg•h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target ƒAUC_0-24/MIC ≥ 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of ≥ 1200 mg/day is needed to achieve sufficient ƒAUC_0-24/MIC ratios.

Conclusions: The model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure.

Keywords: Ciprofloxacin; Critically ill patients; NONMEM; Population pharmacokinetics; Target attainment.

Fig. 1

Box (median, 25th and 75th percentiles) and whisker (10th and 90th percentiles) plots of free (a) trough (ƒC_min), (b) peak (ƒC_max) plasma concentrations, and (c) area under the plasma concentration versus time curves (ƒAUC_0–24) of ciprofloxacin observed in severely ill patients treated with 400 mg one (q24h), two (q12h), and three (q8h) times daily. Filled circles are outliers

Fig. 2

Goodness-of-fit plots of the final model. (a) Observed concentration (OBS) plotted against predicted concentration (PRED). (b) OBS plotted against the individual predicted concentration (IPRED). (c) Conditional weighted residuals plotted against time after dose. (d) CWRES plotted against PRED. The line in A and B represents the line of identity

Fig. 3

Observed ciprofloxacin concentration–time data and the visual predictive check (VPC) of the final model. The blue brackets are the observed concentrations. The red line is the observed median and the two blue lines are the 5th and 95th percentiles of the observed data. The red shaded area is the 95% CI of the model-predicted median and the blue shaded areas are the 95% CIs of the model-predicted 5th and 95th percentiles

Fig. 4

Probabilities of target attainment (PTA) for ciprofloxacin 400 mg (a) q12h, (b) q8h, (c) q6h, 600 mg (d) q12h and (e) q8h. Dotted lines indicate the 95% and 99% confidence intervals (CI). The red reference line represents the pharmacodynamic target of ƒAUC_0–24/MIC ≥ 100