Target concentration intervention is needed for tobramycin dosing in paediatric patients with cystic fibrosis--a population pharmacokinetic study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Two recent papers have been published which have attempted to build a full population pharmacokinetic model for tobramycin in children with cystic fibrosis. * However, neither study was able to provide any information about between-subject variability (BSV) and between-occasion variability (BOV), which is necessary to justify and draw conclusions about the use of target concentration intervention (TCI). * In the publications no simulations were provided to show any new directions or evaluate current therapy.

WHAT THIS STUDY ADDS

• This study provides sound evidence that TCI must be undertaken in this patient group, as the BOV is significantly less than the BSV. * The simulations from this model clearly show that current dosing and monitoring methods will not achieve the necessary targets to maximize the pharmacokinetic-pharmacodynamic relationships of aminoglycosides in this patient group. * The model presented is able to be easily incorporated into Bayesian dose individualization software, e.g. Abbottbase or TCIworks, to achieve dosing targets more accurately.

AIM

The primary aim was to estimate the population pharmacokinetic parameters of once-daily intravenous (i.v.) tobramycin in paediatric cystic fibrosis (CF) patients and to investigate the influence of covariates. The second aim was to assess the need for target concentration intervention (TCI) for tobramycin in this patient group.

METHODS

Retrospective demographic, dosing and concentration data were collected from 35 CF patients (21 female, 14 male) aged 0.5-17.8 years, from whom 318 tobramycin plasma concentrations were available. NONMEM was used to estimate the population pharmacokinetics of tobramycin. Simulations were performed using weight-based dosing with a weight from a covariate distribution model to evaluated current dosing schedules and monitoring practices.

RESULTS

A two-compartment model best described the data with population parameter estimates for clearance of central compartment (CL) of 6.37 l h(-1) per 70 kg; volume of central compartment (V(c)) of 18.7 l per 70 kg; intercompartmental clearance (Q) of 0.393 l h(-1); and volume of peripheral compartment (V(per)) of 1.32 l. The inclusion of total body weight as covariate reduced the random component of between-subject variability in CL from 50.1% to 11.7% and in V(c) from 62.2% to 11.6%. The between-occasion variability on CL was estimated in the final model as 6.5%. Simulations show that one dose does not fit all and TCI and dose adjustment are required.

CONCLUSIONS

This study provides the first pharmacokinetic model of once-daily i.v. tobramycin for the use of target concentration intervention in paediatric CF patients.