JAC Advance Access originally published online on August 21, 2009
Journal of Antimicrobial Chemotherapy 2009 64(4):840-844; doi:10.1093/jac/dkp298
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Original research |
Assessment of micafungin regimens by pharmacokinetic–pharmacodynamic analysis: a dosing strategy for Aspergillus infections
1 Department of Clinical Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan 2 Department of Haematology and Oncology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566 Kyoto, Japan
Received 10 May 2009; returned 17 July 2009; revised 23 July 2009; accepted 27 July 2009
* Corresponding author. Tel: +81-82-257-5296; Fax: +81-82-257-5320; E-mail: ikawak{at}hiroshima-u.ac.jp
Objectives: A pharmacokinetic (PK)–pharmacodynamic (PD) analysis was conducted to assess various micafungin regimens for Candida and Aspergillus infections, as appropriate regimens have not been established, especially for Aspergillus infections.
Methods: Plasma drug concentrations (48 samples from 10 adult patients with haematological malignancies) were determined chromatographically, and used for population PK modelling and Monte Carlo simulation to evaluate the ability of regimens (1 h infusions) to attain genus-dependent PK–PD targets, namely fungistatic and fungicidal targets against Candida spp. [area under the plasma unbound (1%) drug concentration–time curve over 24 h/MIC (fAUC/MIC) = 10 and 20] and an effective concentration target against Aspergillus spp. (plasma unbound drug concentration = 0.05 mg/L).
Results: Mean (variance) values for two-compartment PK model parameters were: clearance, 0.762 L/h (15.4%); volume of central compartment, 9.25 L (24.6%); intercompartmental clearance, 7.02 L/h (fixed); and volume of peripheral compartment, 8.86 L (71.8%). The Monte Carlo simulation demonstrated that 50 mg once daily and 100 mg once daily for the fungistatic and fungicidal targets achieved a >95% probability of target attainment against Candida spp. To achieve such probability against Aspergillus spp., 250 mg once daily or 100 mg twice daily was required.
Conclusions: These results rationalize the approved micafungin dosages for Candida infections (50 mg once daily for prophylaxis and 100–150 mg once daily for treatment), and on the basis of these results we propose a PK–PD-based dosing strategy for Aspergillus infections. A regimen of 200–250 mg/day should be initiated to ensure the likelihood of a favourable outcome. The regimen can be optimized by decreasing the dosing interval.
Keywords: echinocandins , population pharmacokinetics , Monte Carlo simulation