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Target concentration intervention is needed for tobramycin dosing in paediatric patients with cystic fibrosis--a
Stefanie Hennig1, Ross Norris, Carl M J Kirkpatrick
1School of Pharmacy, The University of Queensland, Brisbane, Australia.
Insights
This study developed a tobramycin pharmacokinetic model for children with cystic fibrosis, showing target concentration intervention is necessary due to significant variability. Simulations demonstrate current dosing is insufficient for optimal aminoglycoside therapy.
Area of Science:
- Pharmacokinetics
- Pharmacodynamics
- Pediatric pharmacology
Background:
- Previous population pharmacokinetic models for tobramycin in pediatric cystic fibrosis (CF) patients lacked crucial between-subject variability (BSV) and between-occasion variability (BOV) data.
- These limitations hindered the justification and conclusions regarding target concentration intervention (TCI) and did not offer simulations for therapeutic guidance.
Purpose of the Study:
- To estimate population pharmacokinetic parameters for once-daily intravenous tobramycin in pediatric CF patients.
- To investigate the influence of covariates on tobramycin pharmacokinetics.
- To assess the necessity of TCI for optimizing tobramycin therapy in this population.
Main Methods:
- A retrospective analysis of demographic, dosing, and plasma concentration data from 35 pediatric CF patients.
- Population pharmacokinetic analysis using NONMEM to develop a two-compartment model.
- Simulations were conducted to evaluate current dosing schedules and monitoring practices.
Main Results:
- A two-compartment model described tobramycin pharmacokinetics, with population estimates for clearance (CL) and volume of central compartment (V(c)).
- Total body weight significantly reduced BSV in CL (50.1% to 11.7%) and V(c) (62.2% to 11.6%).
- Between-occasion variability (BOV) on CL was estimated at 6.5%, and simulations indicated that TCI is required for effective dosing.
Conclusions:
- This study presents the first pharmacokinetic model for once-daily intravenous tobramycin specifically for TCI in pediatric CF patients.
- The findings strongly support the implementation of TCI, as BOV is significantly lower than BSV.
- The developed model can be integrated into Bayesian software for more accurate individualized dosing to optimize aminoglycoside therapy.
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.
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