title: Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children.
abstract: Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited pharmacokinetic (PK) data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults. Our objective was to describe the pharmacokinetics of LAmB in children aged 1 to 17 years with suspected or documented IFD. Thirty-five children were treated with LAmB at doses of 2.5 to 10 mg kg-1daily. Samples were taken at baseline and at 0.5- to 2.0-h intervals for 24 h after receipt of the first dose (n = 35 patients) and on the final day of therapy (n = 25 patients). LAmB was measured using high-performance liquid chromatography (HPLC). The relationship between drug exposure and development of toxicity was explored. An evolution in PK was observed during the course of therapy, resulting in a proportion of patients (n = 13) having significantly higher maximum serum concentrations (Cmax) and areas under the concentration-time curve from 0 to 24 h (AUC0-24) later in the course of therapy, without evidence of drug accumulation (trough plasma concentration accumulation ratio of <1.2). The fit of a 2-compartment model incorporating weight and an exponential decay function describing volume of distribution best described the data. There was a statistically significant relationship between mean AUC0-24and probability of nephrotoxicity (odds ratio, 2.37; 95% confidence interval, 1.84 to 3.22; P = 0.004). LAmB exhibits nonlinear pharmacokinetics. A third of children appear to experience a time-dependent change in PK, which is not explained by weight, maturation, or observed clinical factors.
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool, United Kingdom jlestner@liverpool.ac.uk.
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Lestner
authors.affiliation: Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Groll
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Ghaith
authors.initials: G
authors.lastname: Aljayyoussi
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.|Children's National Medical Center and George Washington University School of Medicine and Public Health, Washington, DC, USA.
authors.forename: Nita L
authors.initials: NL
authors.lastname: Seibel
authors.affiliation: Clinical Investigations Branch, Cancer Treatment Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Aziza
authors.initials: A
authors.lastname: Shad
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Corina
authors.initials: C
authors.lastname: Gonzalez
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Lauren V
authors.initials: LV
authors.lastname: Wood
authors.affiliation: Pharmacy Department, National Institutes of Health Clinical Center, Bethesda, Maryland, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Jarosinski
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.|Transplantation-Oncology Infectious Disease Program, Weill Cornell Medical Center, New York, New York, USA.|Department of Pediatrics, Weill Cornell Medical Center, New York, New York, USA.|Department of Microbiology, Weill Cornell Medical Center, New York, New York, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool, United Kingdom.
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
mesh_terms: D000293:Adolescent; D000666:Amphotericin B / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007223:Infant; D000072742:Invasive Fungal Infections / Q000188:drug therapy*; D008297:Male
chemical_list: D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B