title: Population pharmacokinetics of micafungin and its metabolites M1 and M5 in children and adolescents.
abstract: The aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment of Candida infections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and <17 years were obtained from four phase I and two phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve at 24 hours (AUC24) of micafungin within the 10th to 90th percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 μg·h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg of body weight/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC24 target range for invasive candidiasis. Cutoffs of 40 or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for the prevention of invasive candidiasis, the treatment of invasive candidiasis, and the treatment of esophageal candidiasis, respectively, in children aged 4 months to <17 years.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom william.hope@liverpool.ac.uk.
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
authors.affiliation: Astellas Pharma, Northbrook, Illinois, USA.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kaibara
authors.affiliation: Astellas Pharma, Northbrook, Illinois, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Roy
authors.affiliation: Children's Hospital of Orange County, Division of Infectious Disease, Orange, California, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Arrieta
authors.affiliation: Astellas Pharma, Northbrook, Illinois, USA.
authors.forename: Nkechi
authors.initials: N
authors.lastname: Azie
authors.affiliation: Astellas Pharma, Northbrook, Illinois, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kovanda
authors.affiliation: Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
mesh_terms: D000293:Adolescent; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D002177:Candidiasis / Q000188:drug therapy / Q000517:prevention & control; D058365:Candidiasis, Invasive / Q000188:drug therapy / Q000517:prevention & control; D002648:Child; D002675:Child, Preschool; D054714:Echinocandins / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007223:Infant; D055666:Lipopeptides / Q000493:pharmacokinetics*; D008297:Male; D000077551:Micafungin
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077551:Micafungin