JAC Advance Access published online on February 13, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn038
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original research |
Optimized dosage and frequency of cefozopran for patients with febrile neutropenia based on population pharmacokinetic and pharmacodynamic analysis
1 Department of Haematology and Oncology, Kyoto Prefectural University of Medicine Graduate School of Medical Sciences, Kyoto, Japan 2 Department of Microbiology, Kyoto Prefectural Institute of Public Health and Environment, Kyoto, Japan 3 Department of Clinical Pharmacotherapy, Hiroshima University Graduate School, Hiroshima, Japan 4 Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Kyoto, Japan 5 Department of Clinical Molecular Cytogenetics and Laboratory Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Sciences, Kyoto, Japan
Received 3 September 2007; returned 3 December 2007; revised 23 November 2007; accepted 10 January 2008
* Correspondence address. Department of Haematology and Oncology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566 Kyoto, Japan. Tel: +81-75-251-5740; Fax: +81-75-251-5743; E-mail: nomuken{at}koto.kpu-m.ac.jp
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 attainmentT>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.
Key Words: Monte Carlo simulation , haematological malignancies , NONMEM program , Pseudomonas aeruginosa , methicillin-sensitive Staphylococcus aureus