Safety, tolerability, and pharmacokinetics of liposomal amphotericin b in immunocompromised pediatric patients

Nita L. Seibel, Aziza T. Shad, Ihor Bekersky, Andreas H. Groll, Corina Gonzalez, Lauren V. Wood, Paul Jarosinski, Donald Buell, William W. Hope, Thomas J. Walsh

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere01477
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number2
DOIs
Publication statusPublished - Feb 1 2017
Externally publishedYes

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Keywords

  • Antimicrobial safety and tolerability
  • Hematological malignancies
  • Liposomal amphotericin B
  • Pediatrics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Seibel, N. L., Shad, A. T., Bekersky, I., Groll, A. H., Gonzalez, C., Wood, L. V., ... Walsh, T. J. (2017). Safety, tolerability, and pharmacokinetics of liposomal amphotericin b in immunocompromised pediatric patients. Antimicrobial Agents and Chemotherapy, 61(2), [e01477]. https://doi.org/10.1128/AAC.01477-16