Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 61, Issue 2, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01477-16
Keywords
antimicrobial safety and tolerability; hematological malignancies; liposomal amphotericin B; pediatrics; pharmacokinetics
Categories
Funding
- Astellas Pharma USA
- National Institutes of Health
- Astellas
- Novartis
- Merck/Cubist
- Pfizer
- Theravance
- Merck
- Pfizer, Inc.
- Gilead Sciences
- F2G
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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 (AUC(0-24)) values for L-AMB on day 1 increased from 54.7 +/- 32.9 to 430 +/- 566 mu g . 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.
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