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 Ϯ 0.04 mg/dl to 0.63 Ϯ 0.06 mg/dl in the overall population (P ϭ 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 Ϯ 32.9 to 430 Ϯ 566 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 Ն5.0 mg/kg/day.

Extended Dosing Regimens for Fungal Prophylaxis

“…Infusion-related side effects occurred in 11% of 565 infusions, and serum creatinine levels increased significantly in cohorts receiving 5 and 10 mg/kg/day. Pharmacokinetic analyses revealed dose-dependent pharmacokinetics similar to observations in adults and support pediatric dosages similar to those in adults (51,52).…”

Invasive Candidiasis in Infants and Children: Recent Advances in Epidemiology, Diagnosis, and Treatment

“…Liposomal Amphotericin B (L-AMB) is widely used in the treatment of invasive fungal infections in immunocompromised children; however, little is known about its safety and pharmacokinetics in this vulnerable patient population. Seibel and colleagues therefore conducted a study of the safety, tolerability, and pharmacokinetics of L-AMB in 40 immunocompromised children and adolescents in a sequential-dose-escalation, multidose clinical trial [23]. Ten to 13 patients between the ages of 1 and 17 years were enrolled into each of the four dosage cohorts: 2.5, 5.0, 7.5, or 10 mg/kg, to receive empirical antifungal therapy for persistent fever and neutropenia or for the treatment of documented invasive fungal infections.…”

Liposomes: a promising carrier for respiratory syncytial virus therapeutics

“…Liposomes cover a variety of therapeutic areas including viral vaccine, cancer therapy, fungal diseases and analgesics, with more than a dozen liposome formulations already marketed and many are in clinical trials. Liposome formulations suit all ages including infant and older adults [140]. Since more than 90 % of pulmonary material is a lipid, these lipid vesicles should not interfere with the functioning of the respiratory system.…”