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 wee ks of life, undergoing routine therapeutic drug monitoring of their tobramy cin serum levels. The 365 tobramycin concentration measurements obtained we re 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 a ge, and serum creatinine concentration) on clearance and volume of distribu tion was investigated. Forward selection and backward elimination regressio n identified significant covariates. The final pharmacostatistical model wi th 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 rando m-effects parameters, interindividual variability for clearance and for vol ume 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 g ave significant and consistent information on the pharmacokinetics and the determinants of the pharmacokinetic variability of tobramycin in neonates w hen compared with available bibliographic information. Moreover, the final population pharmacokinetic model may be used to design a priori recommendat ions for tobramycin and to improve the dosing readjustments through Bayesia n estimation.