Objectives: The aim of this study was to i) develop a population pharmacokinetic model for tobramycin in paediatric cystic fibrosis (CF) patients ii) investigate the influence of covariates, and iii) use the quantified random and predictable components of variability to asses the need for target concentration intervention for tobramycin (TCI). Methods: Retrospective demographic, dosing and concentration data was collected from 35 cystic fibrosis patients (21 female) aged 0.5 - 17.8 years old from whom 318 tobramycin plasma concentrations were obtained during standard clinical care monitoring. A nonlinear mixed-effect modelling approach (software: NONMEM V, G77, FOCE+I) was used to describe the population pharmacokinetics of tobramycin. Simulations were performed with NONMEM using weight based dosing with a weight from a covariate distribution model and analysed using S-Plus.
Results: A two-compartment model best described the tobramycin data, with population parameter estimates for clearance of central compartment (CL) of 6.37 L/h/70 kg; volume of central compartment (Vc) of 18.7 L/70 kg; inter-compartmental clearance of 0.393 L/h and volume of peripheral compartment of 1.32 L. The inclusion of total body weight allometrically as covariate reduced the random component of between subject variability (BSV) in CL from 50.1% to 11.7% and in Vc from 62.2% to 11.6%. The between occasion variability on CL was estimated in the final model as 6.5%. With the "one dose fits all" approach about 1/3 of the patients would be at risk of over-exposure. A once daily dose of 10 mg/kg tobramycin was found to provide the best compromise between success and over-exposure.
Conclusions: This study provides the first pharmacokinetic model of once-daily IV tobramycin for the use of TCI in paediatric CF patients. Simulations showed that one dose does not fit all and TCI and dose adjustment is required.