Optimized dosage and frequency of cefozopran for patients with febrile neutropenia based on population pharmacokinetic and pharmacodynamic analysis

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.