Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates

Abstract

Objectives: In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates.

Methods: Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients. Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5-12 mg/L) and trough (<0.5 mg/L) concentrations, and cumulative AUC, with the existing and proposed guidelines.

Results: Across the entire neonatal age and weight range, the Dutch National Formulary for Children, the British National Formulary for Children, Neofax and the Red Book resulted in adequate peak but elevated trough concentrations (63%-90% above target). The proposed dosing guideline (4.5 mg/kg gentamicin or 5.5 mg/kg tobramycin) with a dosing interval based on birth weight and post-natal age leads to adequate peak concentrations with only 33%-38% of the trough concentrations above target, and a constant AUC across weight and post-natal age.

Conclusions: The proposed neonatal dosing guideline for gentamicin and tobramycin results in improved attainment of target concentrations and should be prospectively evaluated in clinical studies to evaluate the efficacy and safety of this treatment.

Keywords: NONMEM; aminoglycosides; pharmacokinetics; therapeutic drug monitoring.

Figure 1.

Performance of the proposed dosing guideline versus BNFc guideline during 1 week of treatment summarizing all trough concentrations during treatment. Grey areas represent concentrations under the target value of 0.5 mg/L.

Figure 2.

Performance of the proposed dosing guideline in terms of target peak and trough concentration attainment for gentamicin (top panels) and tobramycin (bottom panels) during 1 week of treatment, plotted against covariates birth weight, current body weight and post-natal age (n = 5000). The broken horizontal lines from top to bottom represent the upper and lower boundaries of target peak concentrations (5–12 mg/L) and the upper limit of the desired trough concentration (≤0.5 mg/L). The bold horizontal lines represent the median predicted concentrations of peak and trough concentrations. The grey layers represent the 90th, 70th, 50th and 30th percentiles of the predicted data.