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Antimicrobial Agents and Chemotherapy, December 2005, p. 5092-5098, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5092-5098.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Amphotericin B Lipid Complex in Neonates{ddagger}

Gudrun Würthwein,1,2,{dagger} Andreas H. Groll,1,{dagger} Georg Hempel,1 Felice C. Adler-Shohet,3 Jay M. Lieberman,3 and Thomas J. Walsh4*

Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, Children's University Hospital, Muenster, Federal Republic of Germany,1 Clinical Pharmacokinetics Section, Coordinating Centre for Clinical Trials (KKS), University Hospital, Muenster, Federal Republic of Germany,2 Millers Children's Hospital, Long Beach, California,3 Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland4

Received 13 June 2005/ Returned for modification 10 July 2005/ Accepted 8 September 2005

The pharmacokinetics of amphotericin B lipid complex (ABLC) were investigated in neonates with invasive candidiasis enrolled in a phase II multicenter trial. Sparse blood (153 samples; 1 to 9 per patient, 1 to 254 h after the dose) and random urine and cerebrospinal fluid (CSF) samples of 28 neonates (median weight [WT], 1.06 kg; range, 0.48 to 4.9 kg; median gestational age, 27 weeks; range, 24 to 41 weeks) were analyzed. Patients received intravenous ABLC at 2.5 (n = 15) or 5 (n = 13) mg/kg of body weight once a day over 1 or 2 h, respectively, for a median of 21 days (range, 4 to 47 days). Concentrations of amphotericin B were quantified as total drug by high-performance liquid chromatography. Blood data for time after dose (TAD) of <24 h fitted best to a one-compartment model with an additive-error model for residual variability, WT0.75 (where 0.75 is an exponent) as a covariate of clearance (CL), and WT as a covariate of volume of distribution (V). Prior amphotericin B, postnatal age, and gestational age did not further improve the model. The final model equations were CL (liters/h) = 0.399 x WT0.75 (interindividual variability, 35%) and V (liters) = 10.5 x WT (interindividual variability, 43%). Noncompartmental analysis of pooled data with a TAD of >24 h revealed a terminal half-life of 395 h. Mean concentrations in the urine after 1, 2, and 3 weeks ranged from 0.082 to 0.430 µg/ml, and those in CSF ranged from undetectable to 0.074 µg/ml. The disposition of ABLC in neonates was similar to that observed in other age groups: weight was the only factor that influenced clearance. Based on these results and previously published safety and efficacy data, we recommend a daily dosage between 2.5 and 5.0 mg/kg for treatment of invasive Candida infections in neonates.

* Corresponding author. Mailing address: Immunocompromised Host Section, National Cancer Institute, National Institutes of Health, CRC-1-5750, 10 Center Drive, Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 402-0575. E-mail: walsht{at}mail.nih.gov.

{ddagger} Supplemental material for this article may be found at http://aac.asm.org/.

{dagger} G.W. and A.H.G. contributed equally to this work.

Antimicrobial Agents and Chemotherapy, December 2005, p. 5092-5098, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5092-5098.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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