British journal of clinical pharmacology · 2026
Physiologically based pharmacokinetic modelling and dose optimization of tedizolid in paediatric patients.
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Li Xueyong, Cheng Yu, Lin Rongqi, Shao Jingping, Lou Luqi, Lin Tian, Wu Xuemei, Qiu Hongqing
Аннотация
AIMS: 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.
METHODS: 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.
RESULTS: The adult and paediatric PBPK models showed good predictive performance, with all predicted AUC and Cmax 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: The adult and paediatric PBPK models showed good predictive performance, with all predicted AUC and Cmax 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.
CONCLUSIONS: 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.