Development of a Population Pharmacokinetic Model of Levofloxacin in Healthy Adults and Identification of Optimal Dosing Regimens

<b>Background/Objectives</b>: Levofloxacin dosing guidelines recommend adjustments only when the creatinine clearance (CrCl) is <50 mL/min. We hypothesized that further dose stratification based on CrCl could improve therapeutic outcomes, even when the CrCl ≥ 50 mL/min. This study aimed to develop a population pharmacokinetic (PK) model of levofloxacin in healthy adults and identify optimal dosing regimens. <b>Methods</b>: In this prospective, open-label study, 12 healthy adults received a single dose of levofloxacin. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry. A population PK model was developed with nonlinear mixed-effects modeling, and Monte Carlo simulations were performed to identify optimal dosing regimens. <b>Results</b>: A two-compartment model with first-order kinetics best described the levofloxacin PK profiles. The CrCl was associated with a variation in clearance and lean body mass, with a variation in peripheral volume of distribution. Simulations identified optimal regimens, defined as those achieving a probability of target attainment of at least 90% for the target unbound 24-hour area under the curve at steady state to minimum inhibitory concentration ratio (<i>f</i>AUC/MIC), which differed by pathogen (≥30 for Gram-positive bacteria; ≥100 for Gram-negative bacteria). For the ratio <i>f</i>AUC/MIC ≥ 30 and an MIC of 0.5 mg/L, 500 mg daily was optimal for patients with a CrCl of 50-89 mL/min. For the ratio <i>f</i>AUC/MIC ≥ 100, 1000 mg daily was required in the same CrCl range and MIC value. <b>Conclusions</b>: The population PK model incorporating CrCl and lean body mass improved the prediction of levofloxacin PKs. Refining current dosing recommendations by incorporating stratified CrCl and MIC values could optimize therapeutic outcomes, particularly for patients with a CrCl ≥ 50 mL/min.