• Kenichi Nomura, Norifumi Morikawa, Kazuro Ikawa, Kayo Ikeda, Yoshiko Fujimoto, Daisuke Shimizu, Kyoko Taniguchi, Kazuho Shimura, Yuko Kanbayashi, Toshiaki Komori, Yosuke Matsumoto, Naohisa Fujita, Chihiro Shimazaki, and Masafumi Taniwaki.
• Department of Haematology and Oncology, Kyoto Prefectural University of Medicine Graduate School of Medical Sciences, Kyoto, Japan. nomuken@koto.kpu-m.ac.jp
• J. Antimicrob. Chemother. 2008 Apr 1; 61 (4): 892-900.

ObjectivesTo 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.MethodsWe 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.ResultsThe 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.ConclusionsOur 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.

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