Physiologically based pharmacokinetic modelling and dose optimization of tedizolid in paediatric patients

Tedizolid is a next-generation oxazolidinone antibiotic approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for tedizolid in adults and paediatric population.

An adult PBPK model was built using GastroPlus®, incorporating physicochemical and pharmacokinetic parameters from the literature. The model was verified against clinical PK data from healthy adults and patients. It was then scaled to paediatric patients aged 2-18 years using age-dependent physiological changes. Paediatric model performance was validated against independent clinical data. Dose simulations evaluated once-daily intravenous and oral regimens targeting a free-drug area under the plasma concentration-time curve (AUC)/minimum inhibitory concentration (MIC) ratio (fAUC/MIC) of ≥3, with ≥90% probability of target attainment (PTA) across MIC values of 0.125-16 mg/L in immunocompetent patients.

The adult and paediatric PBPK models showed good predictive performance, with all predicted AUC and C_max values within the acceptable twofold error range and most observed concentrations falling within the 90% prediction interval. For children aged 2 to <12 years, intravenous and oral doses of ≥4 mg/kg achieved ≥90% PTA at an MIC of 0.5 mg/L. For adolescents aged 12 to <18 years, either a fixed 200 mg dose or a 3 mg/kg dose (intravenous or oral) achieved ≥90% PTA at an MIC of 0.5 mg/L.

The paediatric PBPK model was successfully developed and identified model-derived candidate regimens for immunocompetent paediatric patients with ABSSSIs. These findings support further clinical evaluation of PBPK-guided dose optimization in children.