Development of a Population Pharmacokinetic Model of Levofloxacin in Healthy Adults and Identification of Optimal Dosing Regimens
Abstract
Background/Objectives: 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. Methods: 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. Results: 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 (fAUC/MIC), which differed by pathogen (≥30 for Gram-positive bacteria; ≥100 for Gram-negative bacteria). For the ratio fAUC/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 fAUC/MIC ≥ 100, 1000 mg daily was required…
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