AUTHOR=Chen Yuancheng , Wu Xiaojie , Tsai Chengyuan , Chang Liwen , Yu Jicheng , Cao Guoying , Guo Beining , Shi Yaoguo , Zhu Demei , Hu Fupin , Yuan Jinyi , Liu Yang , Zhao Xu , Zhang Yingyuan , Wu Jufang , Zhang Jing 

TITLE=Integrative population pharmacokinetic/pharmacodynamic analysis of nemonoxacin capsule in Chinese patients with community-acquired pneumonia

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.912962

DOI=10.3389/fphar.2023.912962

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods and Results:</bold> 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<sub>cr</sub>), body weight (BW), sex, disease status and food. Compared to the subject with BW 60 kg, C<sub>max</sub> and <inline-formula id="inf35"><mml:math id="m55" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant="normal">A</mml:mi><mml:mi mathvariant="normal">U</mml:mi><mml:mi mathvariant="normal">C</mml:mi></mml:mrow><mml:mrow><mml:mn mathvariant="normal">0</mml:mn><mml:mi mathvariant="normal">‐</mml:mi><mml:mn mathvariant="normal">24</mml:mn><mml:mo>,</mml:mo><mml:mi mathvariant="normal"> </mml:mi><mml:mi mathvariant="normal">ss</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math></inline-formula> reduced by 24% and 19% in the subject with BW 80 kg, respectively. Compared to the subject with CL<sub>cr</sub> 150 ml/min, <inline-formula id="inf36"><mml:math id="m56" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant="normal">A</mml:mi><mml:mi mathvariant="normal">U</mml:mi><mml:mi mathvariant="normal">C</mml:mi></mml:mrow><mml:mrow><mml:mn mathvariant="normal">0</mml:mn><mml:mi mathvariant="normal">‐</mml:mi><mml:mn mathvariant="normal">24</mml:mn><mml:mo>,</mml:mo><mml:mi mathvariant="normal"> </mml:mi><mml:mi mathvariant="normal">ss</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math></inline-formula> and T<sub>1/2</sub> increased by 28% and 24%, respectively in the subject with CL<sub>cr</sub> 30 ml/min. Compared to the fasted status, T<sub>max</sub> 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<sub>0–24</sub>/MIC and %T &gt; MIC were identified as the optimal PK/PD indices for predicting clinical efficacy. The AUC<sub>0-24</sub>/MIC target was 63.3, 97.8, and 115.7 against <italic>Streptococcus pneumoniae</italic>, <italic>Staphylococcus aureus</italic>, and <italic>Haemophilus influenzae</italic>, respectively. The %T &gt; MIC target was 7.96% against <italic>Klebsiella pneumoniae</italic>. Monte Carlo simulation showed that treatment with nemonoxacin 500 mg q24 h could attain a PK/PD cutoff value higher than the MIC<sub>90</sub> against <italic>S. pneumoniae</italic> and <italic>S. aureus</italic>. 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 <italic>Haemophilus parainfluenzae</italic>, and higher CFR (83%) than 500 mg q24 h.</p><p><bold>Conclusion:</bold> Integrative PK/PD analysis justifies the reliable clinical and microbiological efficacy of nemonoxacin 500 mg q24 h in treating CAP caused by <italic>S. pneumoniae</italic>, <italic>S. aureus</italic>, and <italic>K. pneumoniae</italic>, 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 <italic>H. parainfluenzae</italic> in terms of CFR.</p>