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 (AUC 24 ) 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 g · 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 AUC 24 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. Micafungin is an echinocandin antifungal agent with activity against medically important fungal pathogens such as Candida spp. and Aspergillus spp. (1). It is licensed worldwide for the treatment of adults with invasive candidiasis, the prevention of invasive Candida infections, and the treatment of esophageal candidiasis. A dosage of 100 mg/day is used in adults weighing Ͼ40 kg with candidemia and/or invasive candidiasis. There is no additional benefit in using a higher dosage of 150 mg/day in these patients (2). A dosage of 50 mg/day is used for the prevention of invasive Candida infections in neutropenic patients, while a dosage of 150 mg/day is used for the treatment of esophageal candidiasis.The U.S. Food and Drug Administration (FDA) has approved the use of micafungin for pediatric patients Ͼ4 months of age for the same indications as adults (3). Micafungin is licensed by the European Medicines Agency (EMA) for the treatment of children (including neonates) and adolescents Ͻ16 years of age with invasive candidiasis and as prophylaxis in patients Ͻ16 years of age who are undergoing hematopoietic stem cell transplant or who are expected to have neutropenia (1).The safety and pharmacokinetics (PK) of micafungin in neonates, children, and adolescents have been determined in a number of clinical studies (4, 5). These studies enrolled patients across different age groups and have led to th...

High-Dose Micafungin for Preterm Neonates and Infants with Invasive and Central Nervous System Candidiasis

“…Nonparametric population pharmacokinetic analyses were used, and these permitted the identification of the AST/ALT ratio to be a covariate of micafungin clearance from plasma. The population PK model was further The results of the current study support the conclusions made by Hope and colleagues, who provided the most comprehensive population PK model of micafungin and its metabolites in children and adolescents ranging from 4 months to 16 years of age (19). Their comprehensive population PK analysis included two studies that were the first to suggest that higher micafungin doses (10 to 15 mg/kg/day) may be needed in neonates (20,21).…”

“…Their comprehensive population PK analysis included two studies that were the first to suggest that higher micafungin doses (10 to 15 mg/kg/day) may be needed in neonates (20,21). They demonstrated micafungin clearance to be allometrically scaled to weight and to be a fixed exponent of the AST and total bilirubin concentrations (19). They benchmarked their pediatric doses to values of the micafungin area under the concentration-time curve over 24 h (AUC 24 ) in adults receiving 100 mg/day, with the 10th and 90th percentile expected AUC 24 values being 75.0 mg · h/liter and 139 mg · h/liter, respectively.…”

“…They benchmarked their pediatric doses to values of the micafungin area under the concentration-time curve over 24 h (AUC 24 ) in adults receiving 100 mg/day, with the 10th and 90th percentile expected AUC 24 values being 75.0 mg · h/liter and 139 mg · h/liter, respectively. A 2-mg/kg/day dose in patients ranging from 4 months to less than 2 years of age was expected to achieve a similar AUC 24 distribution in 82.8% of their simulated population (19). Our work suggests that a 3-to 4-mg/kg/day dose in patients weighing 1 kg to 7 kg will achieve AUC 24 values of 75.0 to 139 mg · h/liter in 40.5% to 43.3% of the simulated population.…”

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation

“…19,21 This endpoint matches the micafungin exposure achieved by adult participants who cleared their fungal infection in the large, phase III efficacy trial. 22 There is no established target exposure for Candida prophylaxis, however, IV micafungin 50 mg (1 mg/kg in children) daily was proven effective in preventing fungal infections in 882 adults and children undergoing hematopoietic stem cell transplantation.…”

Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients

“…This has also been confirmed in younger patients (32). The authors suggested this was due to either a higher rate of formation or lower CL of the M-5 metabolite.…”