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: Gudrun Würthwein, Andreas H Groll, Georg Hempel, Felice C Adler-Shohet, Jay M Lieberman, Thomas J Walsh
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 49 Issue 12 Pg. 5092-8 (Dec 2005) ISSN: 0066-4804 [Print] United States
• PMID: 16304177 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study)

Chemical References

• Anti-Infective Agents
• Drug Combinations
• Phosphatidylcholines
• Phosphatidylglycerols
• liposomal amphotericin B
• Amphotericin B

Topics

• Amphotericin B (blood, cerebrospinal fluid, pharmacokinetics, urine)
• Anti-Infective Agents (blood, pharmacokinetics)
• Candida
• Candidiasis (metabolism)
• Drug Combinations
• Humans
• Infant, Newborn (metabolism)
• Models, Biological
• Phosphatidylcholines (blood, cerebrospinal fluid, pharmacokinetics, urine)
• Phosphatidylglycerols (blood, cerebrospinal fluid, pharmacokinetics, urine)