Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients.
Micafungin (FK463) is a new parenteral echinocandin. A multicenter, phase I, open-label, sequential-group dose escalation study was conducted to assess the safety, tolerability, and pharmacokinetics of micafungin in neutropenic pediatric patients. A total of 77 patients stratified by age (2 to 12 and 13 to 17 years) received micafungin. Therapy was initiated at 0.5 mg/kg per day and escalated to higher dose levels of 1.0, 1.5, 2.0, 3.0, and 4.0 mg/kg per day. Micafungin was administered within 24 h of initiating broad-spectrum antibacterial antibiotics for the new onset of fever and neutropenia. The most common overall adverse events in the study population were diarrhea (19.5%), epistaxis (18.2%), abdominal pain (16.9%), and headache (16.9%). Nine patients (12%) experienced adverse events considered by the investigator to be possibly related to the study drug. The most common related events were diarrhea, vomiting, and headache, all occurring in two patients each. There was no evidence of a dose-limiting toxicity as defined within the prespecified criteria of this clinical protocol. There was one death during the study due to septic shock. The pharmacokinetic profiles for micafungin over the 0.5- to 4.0-mg/kg dose range demonstrated dose linearity. Clearance, volume of distribution, and half-life remained relatively constant over the dose range and did not change with repeated administration. The overall plasma pharmacokinetic profile was similar to that observed in adults. However, there was an inverse relation between age and clearance. For patients 2 to 8 years old, clearance was approximately 1.35 times that of patients >/=9 years of age. In summary, micafungin over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile neutropenic pediatric patients displayed linear pharmacokinetics and increased clearance as a function of decreasing age.
Seibel
Nita L
NL
Pediatric Oncology Branch, National Cancer Institute, Bldg. 10, Rm. 13N-240, 10 Center Drive, Bethesda, MD 20892, USA.
Schwartz
Cindy
C
Arrieta
Antonio
A
Flynn
Patricia
P
Shad
Aziza
A
Albano
Edith
E
Keirns
James
J
Lau
Wendi M
WM
Facklam
David P
DP
Buell
Donald N
DN
Walsh
Thomas J
TJ
D000293:Adolescent; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D025141:Drug Resistance, Fungal; D054714:Echinocandins; D005260:Female; D005334:Fever / Q000209:etiology*; D006801:Humans; D055666:Lipopeptides; D008074:Lipoproteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D000077551:Micafungin; D009181:Mycoses / Q000188:drug therapy* / Q000517:prevention & control; D009503:Neutropenia / Q000150:complications*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D008074:Lipoproteins; D010456:Peptides, Cyclic; D000077551:Micafungin