中度肝功能损害者口服苹果酸奈诺沙星胶囊群体药动学/药效学研究及给药方案推荐

Population pharmacokinetic/pharmacodynamic study and dosage regimen recommendation of nemonoxacin malate capsule in moderate hepatic impairment subjects

目的基于群体药动学/药效学(PK/PD)分析,为肝功能损害患者口服苹果酸奈诺沙星胶囊推荐给药方案。方法选取中度肝功能损害者10例和健康受试者按1∶1配对进行对照试验,入选者接受单剂口服苹果酸奈诺沙星胶囊500 mg,通过其血药浓度构建的三房室群体药动学模型预测多剂给药的药动学参数。结合该药对社区获得性肺炎(CAP)临床病原菌的体外药效学数据,以单点估算法计算奈诺沙星对CAP主要病原菌的PK/PD指数,以蒙特卡洛模拟法,分别以游离药物24 h药时曲线下面积/最低抑菌浓度(fAUC0-24h/MIC)≥47.05和≥100作为奈诺沙星对肺炎链球菌和肺炎克雷伯菌的靶值,计算药效学达标概率(PTA)和相应靶值时各累积反应百分率(CFR)。以此评估中度肝功能损害患者口服苹果酸奈诺沙星胶囊500 mg,每日1次,连续给药10 d的给药方案的合理性。结果采用群体药动学模型预测中度肝功能损害和健康受试者口服苹果酸奈诺沙星胶囊10 d后的AUC0-24h分别为(50.94±10.94)mg·h/L和(51.19±10.69)mg·h/L。两组受试者口服苹果酸奈诺沙星胶囊10 d对肺炎链球菌的CFR达95%以上;该药对肺炎链球菌的MIC≤0.5 mg/L时,上述给药方案在两组受试者中的PTA均在98%以上。对于肺炎克雷伯菌,当奈诺沙星目标靶值fAUC/MIC≥100,MIC≤0.25 mg/L时,PTA也可以达到97%以上。两组受试者中奈诺沙星对肺炎克雷伯菌的CFR保持在70%左右。结论 PK/PD结果提示该给药方案预期可在中度肝功能损害受试者中获得与健康受试者相似的微生物学疗效。对于轻中度肝功能损害患者推荐口服苹果酸奈诺沙星胶囊500 mg,每日1次,连续口服7~10 d的给药方案,无需调整剂量。

Objective To provide recommended dosage regimen of nemonoxacin malate capsule in infected patient with hepatic impairment based on population pharmacokinetic/pharmacodynamic analysis.Methods 10 moderate hepatic impairment subjects and healthy subjects were enrolled in a ratio of 1:1 according to parallel control study design.The subjects in both groups were administered a 500 mg single oral dose of nemonoxacin malate capsule.Plasma samples were collected for pharmacokinetic analysis.The three-compartmental model population pharmacokinetic model was established and applied to predict the pharmacokinetic parameters after multiple dose administration.Pharmacodynamics data were obtained from in vitro MIC of nemonoxacin against the bacteria isolated from community acquired pneumonia (CAP) patients.The PK/PD target was determined by single point estimation.The area under the 24 h unchanged drug concentration-time curve/minimum inhibition concentration (fAUC0-24h/MIC) targets (47.05 and 100) against Streptococcus pneumoniae and Klebsiella pneumoniae were employed for the Carlo simulation.The probability of target attainment (PTA) and cumulative fraction of response (CFR) were calculated to evaluate the rational dosage regimen of nemonoxacin malate capsule 500 mg daily for 10 days.Results The predicted AUC0-24h was (50.94±10.94)mg·h/L and (51.19±10.69) mg·h/L after 10-day dosing in moderate hepatic impairment group and healthy control group,respectively.When nemonoxacin was used against Streptococcus pneumoniae (MIC≤0.5 mg/L),the PTA≥98%.When nemonoxacin was administered against Klebsiella pneumoniae (MIC≤0.25 mg/L),the PTA≥97%.However,the CFR was maintained at merely 70% against Klebsiella pneumoniae in both groups.Conclusions The PK/PD results showed that the antimicrobial effect was similar after administration of 500 mg daily for 7-10 days in both moderate hepatic impairment group and healthy group.Dose adjustment is not necessary for nemonoxacin malate capsule in patients with mild or moderate hepatic impairment.