Population kinetics of tobramycin in neonates.

The population kinetics of tobramycin were studied in 140 neonates (100/40 patients for the index/validation groups, respectively) of 30 to 42 weeks' gestational age and 0.8 to 4.25 kg current body weight in their first 2 weeks of life, undergoing routine therapeutic drug monitoring of their tobramycin serum levels. The 365 tobramycin concentration measurements obtained were analyzed by use of NONMEM according to a one-compartment open model with zero-order absorption and first-order elimination. The effect of a variety of demographic, developmental, and clinical factors (gender, height, birth weight, current weight, gestational age, postnatal age, postconceptional age, and serum creatinine concentration) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. The final pharmacostatistical model with influential covariates was as follows (full population): clearance (L/h) = 0.0508 x current weight (kg), multiplied by 0.843 if birth weight was 2.5 kg or less (low-birthweight infants), and volume of distribution (L) = 0.533 x current weight (kg). Using the proportional error model for the random-effects parameters, interindividual variability for clearance and for volume of distribution was determined to be 25.8% and 21.9%, respectively, and the residual variability was 19.2%. In this study, the use of the NONMEM gave significant and consistent information on the pharmacokinetics and the determinants of the pharmacokinetic variability of tobramycin in neonates when compared with available bibliographic information. Moreover, the final population pharmacokinetic model may be used to design a priori recommendations for tobramycin and to improve the dosing readjustments through Bayesian estimation.