A population pharmacokinetic model of gentamicin in paediatric oncology patients to facilitate personalised dosing [PublishAheadOfPrint]

To ensure safe and effective dosing of gentamicin in children therapeutic drug monitoring (TDM) is recommended. TDM utilising Bayesian forecasting software is recommended, but is unavailable as no population model exists that describes the pharmacokinetics of gentamicin in paediatric oncology patients. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalised dosing in paediatric oncology patients. A non-linear mixed effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination, best described gentamicin disposition. The final model included renal function (described by fat-free mass and post-menstrual age) and serum creatinine as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL: 5.77 L/h/70 kg; central volume of distribution: 21.6 L/70 kg, peripheral volume of distribution: 13.8 L/70 kg and intercompartmental clearance: 0.62 L/h/70kg. External evaluation suggested that current models developed in other paediatrics cohorts may not be suitable to use in paediatric oncology patients, as they showed a tendency to over-predict observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean squared error: 46.0% and mean relative prediction error: -3.40 %) and may therefore be useful to personalise gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model.

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