Alternate Day Micafungin Anti-Fungal Prophylaxis In Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation (HSCT): A Pharmacokinetic (PK) Study

Abstract

Disseminated fungal infection is a major cause of morbidity and mortality in children undergoing HSCT. Prophylaxis with amphotericin B can be limited by it's renal toxicity. Oral triazoles are limited by poor absorption, large inter-individual PK variability and hepatic toxicity, leading to breakthrough infections. Intravenous micafungin has a distinct advantage due to its better safety profile specifically in terms of hepatic and renal toxicity, and lack of drug-drug interactions with common medications used in the HSCT setting. We hypothesized that higher dose micafungin (3 mg/kg) every other day will provide drug exposure similar to standard dose (1 mg/kg) given daily, and improve patient compliance at reduced administration costs. Both animal and adult patient data support the use of this approach. Fifteen children (M/F=11/4, age ≤10 y; mean 3.9 y, range 0.6-10 y) with various hematological, metabolic and immune deficiency disorders undergoing HSCT received a single dose of Micafungin (3 mg/kg) intravenously over 1 hour. Dose selection was based on published PK data in pediatric patients (Seibel et al. ntimicrob Agents Chemother, 2005), and exploration of different dosing regimens using Monte Carlo PK/PD simulation. Blood samples were drawn around this dose (pre-dose, at the end of infusion (1 h), and at 1.5, 2, 4, 6, 10, 24, 36 and 48 h post dose) and PK analysis was conducted using standard non-compartmental methods. In addition, we evaluated free AUC/MIC (minimum inhibitory concentration) and Peak/MIC ratios as target pharmacodynamic indices. Micafungin at 3 mg/kg dose was well tolerated in all patients. Measurable plasma concentrations were present in all cases at 48 hours (Table 1). Half-life and clearance observed were comparable to previous pediatric PK data, with clearance being higher than adults as expected. Volume of distribution was higher in our patients compared to published pediatric data, likely due to a larger proportion of very young children in our study cohort (<2 yrs, n=3; 2-5 yrs, n=9; 5-10 yrs, n=3). Our data show measurable plasma levels at 48 hours after a single 3 mg/kg dose of Micafungin. After correction for protein binding, concentrations at the end of the dosing interval during maintenance treatment will remain well above the MIC of most common fungal pathogens. This finding suggests that alternate day Micafungin dosing, as described here, may provide an attractive alternative for antifungal profylaxis in HSCT patients.Table 1Plasma Micafungin Pharmacokinetic ParametersParameters (unit)MeanStandard Deviation (SD)RangeCmax (mg/L)12.52.78.25 – 18.69Cmin (mg/L at 48 hr)0.80.50.27 – 1.99AUC0-24 (hr∗mg/L)128.535.979.29 – 229.18AUC0-48 (hr∗mg/L)164.450.797.46 – 305.16AUC0-INF (hr∗mg/L)180.862.2104.18 – 352.87Cl (ml/hr/kg)17.75.87.89 – 29.62T ½ (h)13.02.19.45 – 16.84Vss (L/kg)0.30.10.22 – 0.48Cmax - peak plasma concentration; Cmin - trough plasma concentration, AUC0-24 area under the plasma concentration-time curve at 24hrs, AUC0-48 area under the plasma concentration-time curve at 48hrs, AUC0-INF area under the plasma concentration-time curve extrapolated to infinity, Cl total body clearance, T ½ elimination half-life, Vss volume of distribution. Open table in a new tab Cmax - peak plasma concentration; Cmin - trough plasma concentration, AUC0-24 area under the plasma concentration-time curve at 24hrs, AUC0-48 area under the plasma concentration-time curve at 48hrs, AUC0-INF area under the plasma concentration-time curve extrapolated to infinity, Cl total body clearance, T ½ elimination half-life, Vss volume of distribution.