Assessing predictive performance of published population pharmacokinetic models of intravenous tobramycin in pediatric patients

Bloomfield, Celeste, Staatz, Christine E., Unwin, Sean and Hennig, Stefanie (2016) Assessing predictive performance of published population pharmacokinetic models of intravenous tobramycin in pediatric patients. Antimicrobial Agents and Chemotherapy, 60 6: 3407-3414. doi:10.1128/AAC.02654-15

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Author Bloomfield, Celeste
Staatz, Christine E.
Unwin, Sean
Hennig, Stefanie
Title Assessing predictive performance of published population pharmacokinetic models of intravenous tobramycin in pediatric patients
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
1098-6596
Publication date 2016-06-01
Sub-type Article (original research)
DOI 10.1128/AAC.02654-15
Open Access Status File (Publisher version)
Volume 60
Issue 6
Start page 3407
End page 3414
Total pages 8
Place of publication Toronto, ON, Canada
Publisher Canadian Center of Science and Education
Language eng
Abstract Several population pharmacokinetic models describe the dose-exposure relationship of tobramycin in pediatric patients. Before the implementation of these models in clinical practice for dosage adjustment, their predictive performance should be externally evaluated. This study tested the predictive performance of all published population pharmacokinetic models of tobramycin developed for pediatric patients with an independent patient cohort. A literature search was conducted to identify suitable models for testing. Demographic and pharmacokinetic data were collected retrospectively from the medical records of pediatric patients who had received intravenous tobramycin. Tobramycin exposure was predicted from each model. Predictive performance was assessed by visual comparison of predictions to observations, by calculation of bias and imprecision, and through the use of simulation-based diagnostics. Eight population pharmacokinetic models were identified. A total of 269 concentration-time points from 41 pediatric patients with cystic fibrosis were collected for external evaluation. Three models consistently performed best in all evaluations and had mean errors ranging from −0.4 to 1.8 mg/liter, relative mean errors ranging from 4.9 to 29.4%, and root mean square errors ranging from 47.8 to 66.9%. Simulation-based diagnostics supported these findings. Models that allowed a two-compartment disposition generally had better predictive performance than those that used a one-compartment disposition model. Several published models of the pharmacokinetics of tobramycin showed reasonable low levels of bias, although all models seemed to have some problems with imprecision. This suggests that knowledge of typical pharmacokinetic behavior and patient covariate values alone without feedback concentration measurements from individual patients is not sufficient to make precise predictions.
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Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
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Created: Fri, 25 Mar 2016, 01:37:23 EST by Dr Stefanie Hennig on behalf of School of Pharmacy