Gudrun Wuerthwein

Population Pharmacokinetics of Amphotericin B Lipid Complex in Neonates

Gudrun Würthwein (1), Georg Hempel (2), Felice C. Adler-Shohet (3), Jay M. Lieberman (3), Thomas J. Walsh (4), and Andreas H. Groll (2)

(1) Coordination Center for Clinical Trials and (2) University Children`s Hospital, - Paediatric Haematology/Oncology -Muenster, FRG; (3) Millers Children’s Hospital, Los Angeles, LA, USA; and (4), Immunocompromised Host Section, NCI, Bethesda, MD, USA

Objectives: Amphotericin B Lipid Complex (ABLC) is as effective but better tolerated as conventional amphotericin B. Little is known, however, about its disposition in neonates. We therefore investigated the plasma pharmacokinetics of ABLC in premature neonates with invasive fungal infections and determined covariates accounting for interindividual variability.

Patients and Methods: Sparse plasma data (153 samples; 1 to 9 per patient, sampled at 1 to 254 h after drug administration) of 28 mostly premature neonates (median weight: 1.06 kg; range: 0.48-4.9; median gestational age: 27 weeks; range: 24-41) enrolled in a multicenter phase II study were analyzed. Patients received either 2.5mg/kg (n=15) or 5mg/kg (n=13) once daily over 1 or 2 hours, respectively, for a median duration of 21days (range: 4-47). Concentrations were measured in whole blood and quantified as total amphotericin by a validated HPLC method. Weight (WT), postnatal age (AGE), gestational age (GA), days on drug, sex, dosage group and prior amphotericin B deoxycholate treatment (DAMP) were documented as potential covariates. Data were analyzed using NONMEM version 5 and XPOSE 3.01.

Results: In a first step, data for time after dose (TAD) £ 24h (n=130) were best fitted to a one compartment model with an additive error model for residual variability, WT¾ as a covariate on clearance (CL) and WT1 as a covariate on volume of distribution (V) (1,2). Potentially significant covariates detected by GAM were DAMP, AGE and GA on CL and DAMP on V. After backward exclusion (p<0.01) none of these covariates significantly decreased the objective function. The final model equations were: CL [l/h] = 0.399xWT¾ (IIV=35%); V [l] = 10.5xWT (IIV=43%).

In a second step, a two compartment model was applied in order to model all data (additional n=23 datapoints for TAD 24-245h). However, the number of data was too small to describe the terminal phase sufficiently. Compartment free analysis of collected observed, dose normalized data with TAD>24h showed a terminal elimination half-life of 395h which is in good agreement with results reported for other pediatric age groups and adults (3,4).

Conclusions: This is the first report of ABLC population pharmacokinetics in premature neonates. Weight was the only covariate that significantly influenced the clearance of amphotericin B from blood.

  1. Holford NHG, Clin Pharmacokinet 1996, 30, 129-32
  2. West GW et al, Science 1997, 276, 122-6
  3. Adedoyin A et al, Antimicrob Agents Chemother 2000, 44, 2900-2
  4. Walsh TJ et al, Antimicrob Agents Chemother 1997, 41, 1944-8

Reference: PAGE 12 (2003) Abstr 406 [www.page-meeting.org/?abstract=406]

Poster: poster