Population pharmacokinetics of levofloxacin in drug-susceptible and drug-resistant tuberculosis patients: Optimal dose suggestion based on renal function

BACKGROUND: Levofloxacin (LFX) has gained attention as an effective drug to reduce treatment duration in tuberculosis (TB). We aimed to evaluate factors related to interindividual variability (IIV) and describe the pharmacokinetics (PK) of LFX in both DS- and DR-TB, as well as explore the optimal dose for TB treatment. METHODS: We included demographics, clinical information, and LFX concentrations from multinational hospitals. All data were utilized for model establishment. The population PK model was built using nonlinear mixed-effects method. Dose simulation was carried out thereafter using Monte Carlo simulation. RESULTS: A one-compartment model with allometric scaling described LFX PK adequately. PK parameters were similar between DS- and DR-TB. eGFR significantly affected CL/F, which decreased by 22 % and 48 % in mild and moderate-severe renal impairment, respectively (normal CL/F: 6.6 L/h). Considering LFX's AUC/MIC target of 146 and epidemiological cut-off value of MIC 0.5 μg/mL, doses of 1000 mg, 1250 mg, and 1500 mg may achieve 90 % probability of target attainment in patients with normal renal function weighing <40 kg, 40-70 kg, and >70 kg, respectively. CONCLUSION: Renal impairment reduced LFX clearance. Doses equal to or greater than 1000 mg may improve AUC/MIC target attainment but require cautious use considering safety and clinical efficacy.