title: Safety, Tolerability, and Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Pediatric Patients.
abstract: The safety, tolerability, and pharmacokinetics of the liposomal formulation of amphotericin B (L-AMB) were evaluated in 40 immunocompromised children and adolescents. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study with 10 to 13 patients in each of the four dosage cohorts. Each cohort received daily dosages of 2.5, 5.0, 7.5, or 10 mg of amphotericin B in the form of L-AMB per kg of body weight. Neutropenic patients between the ages of 1 and 17 years were enrolled to receive empirical antifungal therapy or treatment of documented invasive fungal infections. The pharmacokinetic parameters of L-AMB were measured as those of amphotericin B by high-performance liquid chromatography and calculated by noncompartmental methods. There were nine adverse-event-related discontinuations, four of which were related to infusions. Infusion-related side effects occurred for 63 (11%) of 565 infusions, with 5 patients experiencing acute infusion-related reactions (7.5- and 10-mg/kg dosage levels). Serum creatinine levels increased from 0.45 ± 0.04 mg/dl to 0.63 ± 0.06 mg/dl in the overall population (P = 0.003), with significant increases in dosage cohorts receiving 5.0 and 10 mg/kg/day. At the higher dosage level of 10 mg/kg, there was a trend toward greater hypokalemia and vomiting. The area under the concentration-time curve from 0 to 24 h (AUC0-24) values for L-AMB on day 1 increased from 54.7 ± 32.9 to 430 ± 566 μg · h/ml in patients receiving 2.5 and 10.0 mg/kg/day, respectively. These findings demonstrate that L-AMB can be administered to pediatric patients at dosages similar to those for adults and that azotemia may develop, especially in those receiving ≥5.0 mg/kg/day.
authors.affiliation: Children's National Medical Center and George Washington University School of Medicine and Public Health, Washington, DC, USA.|Clinical Investigations Branch, Cancer Treatment Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Nita L
authors.initials: NL
authors.lastname: Seibel
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, MedStar Georgetown University Hospital, Washington, DC, USA.
authors.forename: Aziza T
authors.initials: AT
authors.lastname: Shad
authors.affiliation: Astellas Pharma USA, Inc., Deerfield, Illinois, USA.
authors.forename: Ihor
authors.initials: I
authors.lastname: Bekersky
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.|Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Groll
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, MedStar Georgetown University Hospital, Washington, DC, USA.
authors.forename: Corina
authors.initials: C
authors.lastname: Gonzalez
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Lauren V
authors.initials: LV
authors.lastname: Wood
authors.affiliation: Pharmacy Department, The NIH Clinical Center, Bethesda, Maryland, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Jarosinski
authors.affiliation: Astellas Pharma USA, Inc., Deerfield, Illinois, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Buell
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA thw2003@med.cornell.edu.|Transplantation-Oncology Infectious Disease Program, Weill Cornell Medicine, New York City, New York, USA.|Department of Pediatrics, Weill Cornell Medicine, New York City, New York, USA.|Department of Microbiology and Immunology, Weill Cornell Medicine, New York City, New York, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007262:Infusions, Intravenous; D008297:Male; D009503:Neutropenia / Q000188:drug therapy / Q000382:microbiology; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B; D003404:Creatinine
keywords: antimicrobial safety and tolerability; hematological malignancies; liposomal amphotericin B; pediatrics; pharmacokinetics