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Micafungin antifungal prophylaxis in children undergoing HSCT: can we give higher doses, less frequently? A
Sharat Chandra1,2, Tsuyoshi Fukuda2,3, Kana Mizuno3
1Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Background:
Micafungin has a distinct advantage for antifungal prophylaxis in HSCT owing to its better safety profile, specifically in terms of hepatic and renal toxicity. In children, prophylactic micafungin is given as either 1 mg/kg every day or 3 mg/kg every other day.
Objectives:
We performed a prospective single-centre observational study that investigated the pharmacokinetics (PK) of a single 5 mg/kg dose of micafungin in young children undergoing HSCT, to ascertain the eventual feasibility of twice-weekly prophylactic administration.
Methods:
Nine children, ≤10 years of age undergoing HSCT, were enrolled and received a single intravenous dose of 5 mg/kg micafungin. Blood samples were obtained for PK analysis. Micafungin plasma concentration of >0.2 mg/L was chosen for target attainment (i.e. considered adequate prophylactic concentration). In addition, a population PK model was developed based on current and our previous PK study data. We also evaluated PK model-based simulation of PK profiles and target attainment using Monte Carlo simulation, for several dosing scenarios.
Results:
Mean clearance was 15.3 mL/h/kg (range 11.0-21.4 mL/h/kg) and the mean elimination half-life was 11.6 h (range 7.8-16.6 h). The mean concentration at 96 h was 0.11 mg/L (range 0.03-0.26 mg/L). Eleven percent (n = 1) of patients achieved target attainment at the end of 96 h. Simulation data showed that 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies achieved at least 99% and 81% target attainment, respectively, whereas a 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively.
Conclusions:
Micafungin at 5 mg/kg dosing did not achieve target attainment at the end of 96 h for antifungal prophylaxis in children undergoing HSCT. Simulation data suggest that a dosing strategy of micafungin at 5 mg/kg every 72 h is more likely to achieve target attainment in children with a higher body weight in comparison with children with a lower body weight. A cautious approach is advisable when using a high, but less frequent, dosing strategy in very young children.
Insights
A 5 mg/kg dose of micafungin did not achieve adequate antifungal prophylaxis levels in children undergoing HSCT. Simulation suggests higher body weight may improve target attainment with less frequent dosing.
Area of Science:
- Pharmacology
- Pediatric Hematology/Oncology
- Infectious Diseases
Background:
- Micafungin offers a favorable safety profile for antifungal prophylaxis in hematopoietic stem cell transplantation (HSCT), with lower risks of hepatic and renal toxicity.
- In pediatric HSCT, micafungin is typically administered at 1 mg/kg daily or 3 mg/kg every other day for prophylaxis.
Purpose of the Study:
- To investigate the pharmacokinetics (PK) of a single 5 mg/kg micafungin dose in young children undergoing HSCT.
- To assess the feasibility of a twice-weekly prophylactic administration schedule for micafungin in this population.
Main Methods:
- A prospective, single-center observational study involving nine children (≤10 years) undergoing HSCT.
- Administration of a single 5 mg/kg intravenous micafungin dose, with blood samples collected for PK analysis.
- Development of a population PK model and Monte Carlo simulations to evaluate various dosing scenarios and target attainment (>0.2 mg/L).
Main Results:
- The mean micafungin clearance was 15.3 mL/h/kg, with a mean elimination half-life of 11.6 hours.
- Only 11% of patients achieved the target trough concentration (>0.2 mg/L) at 96 hours post-dose.
- Simulations indicated that daily 1 mg/kg and alternate-day 3 mg/kg dosing achieved >99% and 81% target attainment, respectively. A 5 mg/kg every 72 hours strategy showed variable attainment based on body weight (64-84%).
Conclusions:
- A single 5 mg/kg dose of micafungin is insufficient for achieving adequate antifungal prophylaxis levels in children undergoing HSCT.
- Simulations suggest that less frequent dosing (e.g., every 72 hours) may be more effective in heavier children, but cautious use is advised in very young children.
- Current standard dosing regimens (1 mg/kg daily or 3 mg/kg alternate-day) are more reliable for achieving target concentrations in pediatric HSCT prophylaxis.
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