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Background: Disseminated fungal infection is a major cause of morbidity and mortality in children undergoing HCT. Anti-fungal prophylaxis with intravenous micafungin has a distinct advantage over amphotericin-B and oral triazoles 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 HCT setting. Currently, children who receive prophylactic micafungin are given daily dosing (1mg/kg/dose) or alternate day dosing (3mg/kg/dose). We hypothesized that higher dose micafungin (5 mg/kg) every 4 days will provide effective anti-fungal prophylaxis, and improve patient compliance (with essentially twice a week dosing regimen).
Objectives: To examine micafungin PK when given at 5mg/kg dose for anti-fungal prophylaxis to children undergoing HCT.
Methods: Nine children with various hematological, metabolic and immune deficiency disorders undergoing HCT received a single dose of micafungin (5 mg/kg) intravenously over 1 hour. Dose selection was based on published PK data in pediatric neutropenia patients (Seibel et al. 2005), our alternate day micafungin PK study (Mehta et al. 2010), along with Monte Carlo PK/PD simulation. Blood samples were drawn around the micafungin infusion and at regular intervals until 96 hours after. Plasma concentration data were analyzed by noncompartmental (WinNonlin) and population PK analysis (NONMEM).
Results: Micafungin at 5 mg/kg dose was well tolerated in all subjects along with measurable plasma concentrations at 96 hours (Table 1). PK was best described by a 2-compartment model in all subjects (Figure 1). The mean concentration at 96 hours was 0.11 μg/mL (Range: 0.03-0.26 μg/mL). Concentrations at the end of the 96 hours remain above the minimum inhibitory concentration (MIC) of susceptible fungal pathogens (MIC >0.2 µg/ml) in 1 patient (11%) only. However, target concentrations were achieved in 7/9 (78%) patients at the end of 72 hours. When accounted for the post-antifungal effect, all 9 (100%) patients were in the goal range at the end of 72 hours.
Conclusion: Our data suggest that although micafungin at 5 mg/kg dosing generates suboptimal levels at the end of 4 days, observed levels at the end of 3 days were in the target range, to cover susceptible fungal pathogens and provide an attractive alternative for anti-fungal prophylaxis in children undergoing HCT.
This study was supported by an unrestricted research grant from Astellas Pharma US, Inc. The sponsor did not participate in study design or interpretation of results.
Table 1: Micafungin concentrations
Patient | At 24 hrs (µg/ml) | At 48 hrs (µg/ml) | At 72 hrs (µg/ml) | At 96 hrs (µg/ml) |
Mean | 4.60 | 1.19 | 0.34 | 0.11 |
SD | 1.07 | 0.36 | 0.15 | 0.08 |
Figure 1: PK profile of micafungin
