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Antimicrobial Agents and Chemotherapy, October 2007, p. 3714-3719, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00398-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Micafungin in Pediatric Patients and Implications for Antifungal Dosing

William W. Hope,^1,2 Nita L. Seibel,³ Cindy L. Schwartz,⁴ Antonio Arrieta,⁵ Patricia Flynn,⁶ Aziza Shad,⁷ Edythe Albano,⁸ James J. Keirns,⁹ Donald N. Buell,⁹ Tawanda Gumbo,² George L. Drusano,² and Thomas J. Walsh^1*

Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,¹ Emerging Pathogen Section, Ordway Research Institute, Albany, New York 12208,² Center for Cancer and Blood Disorders, Children's National Medical Center, George Washington University School of Medicine and Public Health, Washington, D.C. 20010,³ Warren Albert Medical School of Brown University, Providence, Rhode Island 02903,⁴ Children's Hospital of Orange County, Orange, California 92868-3874,⁵ Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,⁶ Department of Pediatrics, Division of Pediatric Hematology/Oncology, Georgetown University Medical Center, Washington, D.C. 20007-2197,⁷ The Children's Hospital, Denver, Colorado 80218,⁸ Astellas Pharma US, Deerfield, Illinois⁹

Received 23 March 2007/ Returned for modification 4 May 2007/ Accepted 9 July 2007

The echinocandins potentially have an important role in treatment of infections caused by Candida spp. and Aspergillus spp. in immunocompromised children. However, there are no population pharmacokinetic models of the echinocandins for pediatric patients. The safety and descriptive pharmacokinetics of micafungin in children were recently reported. However, a population pharmacokinetic model in children is needed in order to accurately determine the dosage of micafungin that produces an equivalent magnitude of drug exposure to that observed in adults. In order to explore the effect of weight on micafungin pharmacokinetics, a standard two-compartment pharmacokinetic model, a linear model, and an allometric power model were developed. For all three models, the fit to the data was excellent, with comparable measures of precision and bias. However, the superior log-likelihood value of the allometric power model suggested that it best reflected the data and was therefore chosen for a more detailed analysis of the magnitude and pattern of drug exposure which develop following the administration of micafungin. The allometric power model suggested that clearance in smaller children is higher than that predicted on the basis of weight alone. Consequently, a degree of dosage increase is required in smaller children to ensure comparable levels of drug exposure to those observed in larger children and adults. The allometric power model developed in this study enables identification of pediatric dosage regimens of micafungin which, based upon Monte Carlo simulations, result in equivalent drug exposures to those observed in adults, for which antifungal efficacy has been established.

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* Corresponding author. Mailing address: Pediatric Oncology Branch, NCI/NIH, CRC Room 1-5750, 10 Center Dr., Bethesda, MD 20892-1100. Phone: (301) 402-0023. Fax: (301) 480-2308. E-mail: walsht{at}mail.nih.gov

Published ahead of print on 16 July 2007.

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Antimicrobial Agents and Chemotherapy, October 2007, p. 3714-3719, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00398-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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