title: Population pharmacokinetics of amphotericin B lipid complex in neonates.
abstract: 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 WT(0.75) (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 microg/ml, and those in CSF ranged from undetectable to 0.074 microg/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.
authors.affiliation: Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, Children's University Hospital, Muenster, Federal Republic of Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Würthwein
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Groll
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
authors.forename: Felice C
authors.initials: FC
authors.lastname: Adler-Shohet
authors.forename: Jay M
authors.initials: JM
authors.lastname: Lieberman
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000666:Amphotericin B / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics*; D002175:Candida; D002177:Candidiasis / Q000378:metabolism; D004338:Drug Combinations; D006801:Humans; D007231:Infant, Newborn / Q000378:metabolism*; D008954:Models, Biological; D010713:Phosphatidylcholines / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine; D010715:Phosphatidylglycerols / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000890:Anti-Infective Agents; D004338:Drug Combinations; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; C068538:liposomal amphotericin B; D000666:Amphotericin B