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Antimicrobial Agents and Chemotherapy, November 2008, p. 4043-4049, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00569-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Fluconazole in Young Infants{triangledown}

K. C. Wade,1,2* D. Wu,2 D. A. Kaufman,3 R. M. Ward,4 D. K. Benjamin Jr.,5 J. E. Sullivan,6 N. Ramey,7 B. Jayaraman,2 K. Hoppu,8 P. C. Adamson,2 M. R. Gastonguay,9 J. S. Barrett,2 on behalf of the NICHD Pediatric Pharmacology Research Unit Network{dagger}

Department of Pediatrics, Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,1 Department of Pediatrics, Division of Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,2 Department of Pediatrics, University of Virginia, Charlottesville, Virginia,3 Department of Pediatrics, University of Utah, Salt Lake City, Utah,4 Department of Pediatrics and Duke Clinical Research Institute, Duke University, Durham, North Carolina,5 Department of Pediatrics, University of Louisville, Louisville, Kentucky,6 KAI Research, Inc,7 Hospital for Children and Adolescents and Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland,8 Metrum Institute, Tariffville, Connecticut9

Received 1 May 2008/ Returned for modification 25 August 2008/ Accepted 9 September 2008

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)–4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

* Corresponding author. Mailing address: Division of Neonatology, Children's Hospital of Philadelphia, 34th Street and Civic Center Blvd., Philadelphia, PA 19104. Phone: (215) 829-3301. Fax: (215) 829-7211. E-mail: wade{at}email.chop.edu

{triangledown} Published ahead of print on 22 September 2008.

{dagger} Members of the PPRU fluconazole study group are listed in Acknowledgements.

Antimicrobial Agents and Chemotherapy, November 2008, p. 4043-4049, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00569-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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  • Laer, S., Barrett, J. S., Meibohm, B. (2009). The In Silico Child: Using Simulation to Guide Pediatric Drug Development and Manage Pediatric Pharmacotherapy. J Clin Pharmacol 49: 889-904 [Abstract] [Full Text]  


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