Population pharmacokinetics of oral levofloxacin 500 mg once-daily dosage in community-acquired lower respiratory tract infections: results of a prospective multicenter study in China

This study aimed to explore the pharmacokinetic features of levofloxacin (LVFX) in Chinese patients with infections and to confirm oral LVFX 500 mg once daily as an optimal treatment regimen based on pharmacokinetic-pharmacodynamic (PK-PD) analysis. A total of 1052 plasma samples from 164 Chinese adult patients with communityacquired lower respiratory tract infections (CALRTIs) and 18 healthy volunteers were used for population PK analysis. LVFX 500-mg tablets were given once daily. A nonlinear mixed effects model (NONMEM) program was used for population PK model-building and a two-compartment model with first-order absorption process was established. Creatinine clearance (CLcr) and body weight were identified as intrinsic factors which significantly affected oral clearance (CLt/F) and the apparent volume of distribution of the central compartment (V1/F), respectively. The final model is described as follows: CLt/F (l/h) = (8.97 + 0.917 × (CLcr (ml/min) − 100.92) × 60/1000) × exp (ηCLt/F). V1/F (l) = (85.3 + 1.22 × (weight (kg) − 60.75)) × exp (ηV1/F). Q/F (l/h) = 0.351. V2/F (l) = 6.81. ka (h−1) = 1.44 × exp(ηka). Based on the population PK model, mean Cmax and AUC0–24h in CALRTI patients were estimated as 5.13 µg/ml and 58.98 µg·h/ml, respectively. A subgroup analysis showed that patients with mild renal dysfunction (50 ml/min ≤ CLcr < 80 ml/min) had 34% higher AUC0–24h values compared to patients with normal renal function (CLcr ≥ 80 ml/min). Postmodeling simulation using final population PK estimates also showed that Cmax and AUC0–24h increased markedly in patients with severe renal dysfunction. The results indicate that LVFX dosage adjustment should be individualized on the basis of the CLcr, especially in those with CLcr less than 50 ml/min. None of the PK parameters had any correlation with the occurrence of adverse events. PK-PD analysis indicated that, in patients treated with LVFX 500 mg once daily, the AUC0–24h/MIC ratio exceeded the target for those major CALRTI pathogens isolated. In addition, the Cmax/MIC ratio reached 5 for Streptococcus pneumoniae, indicating that the emergence of LVFX-resistant S. pneumoniae could be prevented during the therapy with this dosage regimen. These results demonstrate that oral LVFX 500 mg once daily has favorable PK parameters and PK-PD features in patients with CALRTIs, and the results strongly support this dosage regimen for the treatment of CALRTI.