LAUSR

Introduction: Nemonoxacin is an innovative quinolone antibiotic for treatment of community-acquired pneumonia (CAP). As more data are available from clinical studies, it is necessary to perform an integrative pharmacokinetic/pharmacodynamic (PK/PD) analysis to support and justify the optimal dosing regimen of nemonoxacin in clinical practice. Methods and Results: We developed a population PK model using non-linear mixed effect model based on the data of 195 Chinese subjects receiving nemonoxacin in phase I to III clinical trials. The base model was a standard two-compartment PK model defined by clearance (12 L/h) and central volume of distribution (86 L). Covariates included creatinine clearance (CLcr), body weight (BW), sex, disease status and food. Compared to the subject with BW 60 kg, Cmax and A U C 0 ‐ 24 ,   ss reduced by 24% and 19% in the subject with BW 80 kg, respectively. Compared to the subject with CLcr 150 ml/min, A U C 0 ‐ 24 ,   ss and T1/2 increased by 28% and 24%, respectively in the subject with CLcr 30 ml/min. Compared to the fasted status, Tmax of nemonoxacin increased by 1.2 h in the subject with fed status. Effects of sex and disease status on PK parameters were small (change of PK parameters ≤19%). AUC0–24/MIC and %T > MIC were identified as the optimal PK/PD indices for predicting clinical efficacy. The AUC0-24/MIC target was 63.3, 97.8, and 115.7 against Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, respectively. The %T > MIC target was 7.96% against Klebsiella pneumoniae. Monte Carlo simulation showed that treatment with nemonoxacin 500 mg q24 h could attain a PK/PD cutoff value higher than the MIC90 against S. pneumoniae and S. aureus. The corresponding cumulative fraction of response (CFR) was greater than 93%, while nemonoxacin 750 mg q24 h would provide higher PK/PD cutoff value against Haemophilus parainfluenzae, and higher CFR (83%) than 500 mg q24 h. Conclusion: Integrative PK/PD analysis justifies the reliable clinical and microbiological efficacy of nemonoxacin 500 mg q24 h in treating CAP caused by S. pneumoniae, S. aureus, and K. pneumoniae, irrespective of patient sex, mild renal impairment, empty stomach or not. However, nemonoxacin 750 mg q24 h would provide better efficacy than 500 mg q24 h for the CAP caused by H. parainfluenzae in terms of CFR.