生理药动学模型结合蒙特卡洛模拟用于优化替加环素在成人医院获得性肺炎患者中的应用

Physiologically based pharmacokinetic modeling combined with Monte Carlo simulation for optimizing tigecycline dosing in patients with hospital-acquired pneumonia

目的探讨替加环素用于经验性以及目标性治疗成人医院获得性肺炎的合适给药方案。方法通过建立替加环素的生理药动学模型,并与蒙特卡洛模拟结合。结果替加环素用于经验性治疗成人医院获得性肺炎时,给予100 mg q12h(首剂200 mg)较合适。用于目标性治疗时,当其对鲍曼不动杆菌或肺炎克雷伯菌的MIC≤0.5 mg·L^(-1)时,可予说明书推荐剂量,即50 mg q12h(首剂100 mg);当0.5 mg·L^(-1)<MIC≤0.1 mg·L^(-1)时,可予剂量100 mg q12h(首剂200 mg);当1 mg·L^(-1)<MIC≤0.2 mg·L^(-1)时,可予剂量150 mg q12h(首剂300 mg)。结论建立的替加环素生理药动学模型能准确预测相应人群的药动学参数,并与蒙特卡洛模拟结合,可用于成人医院获得性肺炎患者给药方案的优化。

AIM To explore an optimal dosage regimen of tigecycline for empirical and targeted therapy of hospital-acquired pneumonia(HAP).METHODS A physiologically based pharmacokinetic(PBPK)model of tigecycline was developed,and was subjected to Monte Carlo simulation(MCS).RESULTS A loading dose of 200 mg,followed by 100 mg q12 h,might be reasonable when tigecycline was used for empirical HAP therapy caused by A.baumannii and K.pneumoniae.For targeted therapy,the registered dosage appeared to be only effective at MIC≤0.5 mg·L^(-1).The adjusted regimens of a loading dose of 200 mg,followed by 100 mg q12 h,were predicted to be effective at MIC≤1 mg·L^(-1).And also,300 mg tigecycline IV loading dose,followed by 150 mg q12 h,was predicted to be effective with elevated resistance(MIC≤2 mg·L^(-1)).CONCLUSION The tigecycline PBPK model can accurately predict pharmacokinetic(PK)parameters of the corresponding populations.Combining PBPK modeling with MCS may optimize clinical dosage regimens of tigecycline in patients with HAP.