Physiologically based pharmacokinetic modelling of levofloxacin as a tool for paediatric dose optimization
Abstract
Aims Levofloxacin (LFX) is critical for paediatric community‐acquired pneumonia (CAP) and multidrug‐resistant tuberculosis (MDR‐TB). Current guideline doses may provide suboptimal exposure in younger children. This study aims to develop a paediatric physiologically based pharmacokinetic (PBPK) model to evaluate current guidelines and propose optimized oral regimens. Methods An adult PBPK model was developed and verified against 21 adult clinical studies. The model was scaled to virtual paediatric populations (0.5–16 years old) using age‐dependent physiology and verified against paediatric data. Simulations assessed probability of target attainment (PTA ≥ 90%) for CAP ( f AUC ss,0–24 /MIC ≥ 33.7) and MDR‐TB ( f AUC ss,0–24 /MIC ≥ 100). Results The adult model was verified (test dataset geometric fold error (GMFE): 1.04; mean relative deviation [MRD]: 1.33). The scaled paediatric model accurately predicted observed concentrations (86% within 90% prediction interval). For CAP, guideline doses (10 mg/kg QD) were inadequate in children >5 years (PTA: 46.7%–63%); optimized regimens (e.g., 14 mg/kg QD for 5–10 years) achieved PTA ≥ 90.4%. For MDR‐TB, WHO‐recommended doses (~15–20 mg/kg/day) caused severe underexposure in children 90%. Conclusions Current paediatric LFX guidelines are suboptimal for CAP in children >5 years of age and critically inadequate for MDR‐TB targets in children <24 kg. This PBPK model provides rational, age‐specific oral dosing strategies to improve target…
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