Nomura Kenichi, Morikawa Norifumi, Ikawa Kazuro, Ikeda Kayo, Fujimoto Yoshiko, Shimizu Daisuke, Taniguchi Kyoko, Shimura Kazuho, Kanbayashi Yuko, Komori Toshiaki, Matsumoto Yosuke, Fujita Naohisa, Shimazaki Chihiro, Taniwaki Masafumi
Department of Haematology and Oncology, Kyoto Prefectural University of Medicine Graduate School of Medical Sciences, Kyoto, Japan.
J Antimicrob Chemother. 2008 Apr;61(4):892-900. doi: 10.1093/jac/dkn038. Epub 2008 Feb 13.
To establish a cefozopran (a fourth-generation cephem) population pharmacokinetic model using patient data and use it to explore alternative dosage regimens that could optimize the currently used dosing regimen to achieve higher likelihood of pharmacodynamic exposure against pathogenic bacteria.
We conducted a prospective clinical trial of cefozopran for haematological patients with febrile neutropenia (FN). Twenty-two patients (30 episodes) were selected to receive intravenous cefozopran every 8 h on a daily basis. We gathered concentration data and performed the NONMEM program. The Monte Carlo simulation was performed to assess the pharmacodynamic exposure based on the population pharmacokinetics and MIC.
The NONMEM program demonstrated that a two-compartment model provided a best fit for the data, that is, CL of 4.62 (L/h), V1 of 10.3 (L), Q of 4.47 (L/h), and V2 of 4.48 (L). On the basis of the Japanese national surveillance findings for Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus, coagulase-negative Staphylococcus, viridans group streptococci, Escherichia coli and Klebsiella pneumoniae, Monte Carlo simulation data showed that probability of target attainment(T>MIC = 70%) is 67% to 97% for dosing every 8 h, and 48% to 88% for dosing every 12 h. For the patients in whom the efficacy of cefozopran could be evaluated, 17 of 22 patients (77.2%) survived the episode of FN without requiring further antibacterial treatment.
Our study proved that Monte Carlo simulation based on population pharmacokinetics can determine optimized dosage and method. The optimal regimen for this cephem was found to be three times daily.
利用患者数据建立头孢唑兰（一种第四代头孢菌素）群体药代动力学模型，并利用该模型探索替代给药方案，以优化当前使用的给药方案，从而提高对病原菌进行药效学暴露的可能性。
我们对血液系统发热性中性粒细胞减少症（FN）患者进行了一项头孢唑兰前瞻性临床试验。选择22例患者（30个疗程），每天每8小时静脉注射头孢唑兰。我们收集了浓度数据并运行了NONMEM程序。基于群体药代动力学和最低抑菌浓度（MIC）进行蒙特卡洛模拟，以评估药效学暴露情况。
NONMEM程序显示，二室模型最适合该数据，即清除率（CL）为4.62（L/h），中央室容积（V1）为10.3（L），转运速率（Q）为4.47（L/h），周边室容积（V2）为4.48（L）。根据日本全国对铜绿假单胞菌、甲氧西林敏感金黄色葡萄球菌、凝固酶阴性葡萄球菌、草绿色链球菌、大肠埃希菌和肺炎克雷伯菌的监测结果，蒙特卡洛模拟数据显示，每8小时给药一次时，达到目标的概率（T>MIC = 70%）为67%至97%，每12小时给药一次时为48%至88%。对于可评估头孢唑兰疗效的患者，22例患者中有17例（77.2%）在FN发作期间存活，无需进一步抗菌治疗。
我们的研究证明，基于群体药代动力学的蒙特卡洛模拟可以确定优化的剂量和方法。发现该头孢菌素的最佳给药方案为每日三次。
