In:
Frontiers in Pharmacology, Frontiers Media SA, Vol. 14 ( 2023-2-28)
Abstract:
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 (CL cr ), body weight (BW), sex, disease status and food. Compared to the subject with BW 60 kg, C max 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 CL cr 150 ml/min, A U C 0 ‐ 24 , ss and T 1/2 increased by 28% and 24%, respectively in the subject with CL cr 30 ml/min. Compared to the fasted status, T max 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%). AUC 0–24 /MIC and %T & gt; MIC were identified as the optimal PK/PD indices for predicting clinical efficacy. The AUC 0-24 /MIC target was 63.3, 97.8, and 115.7 against Streptococcus pneumoniae , Staphylococcus aureus , and Haemophilus influenzae , respectively. The %T & gt; 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 MIC 90 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.
Type of Medium:
Online Resource
ISSN:
1663-9812
DOI:
10.3389/fphar.2023.912962
DOI:
10.3389/fphar.2023.912962.s001
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2023
detail.hit.zdb_id:
2587355-6
SSG:
15,3
Permalink
