High doses of micafungin are advocated in neonates with systemic candidiasis but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, 3 with meningitis, were treated for at least 14 days with 8 to 15 mg/kg/day of intravenous micafungin. Plasma concentrations (4 measurements) were determined after the third dose and cerebrospinal-fluid (CSF) concentrations were also obtained in three patients. Population PK analyses were used to identify the optimal model and further validated using external data (n=5). The safety of micafungin was assessed through liver and kidney function biomarkers. The mean (standard deviation) age and weight at administration was 2.33 (1.98) months and 3.24 (1.61) kg, respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase ratio. The CSF was sampled in three patients with observed concentrations between 0.80-1.80 mg/L. The model predicted mean (SD) micafungin AUC24 values is 336 (165) h•mg/L with a 10 mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection but five had neurologic impairments. Among transaminases, alkaline phosphatase measurements were significantly higher post-treatment with a geometric mean ratio [90% confidence interval] of 1.17 [1.01, 1.37]. Furthermore, marked elevations in gamma-glutamyl transferase (GGT) was observed in three patients treated with 10-15 mg/kg/day doses and improvement in GGT was noted after dose reduction. Higher weight-based doses of micafungin are generally well tolerated in neonates and infants and achieve pharmacokinetic profiles predictive of effect.

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

FALCONE, MARCO;
2016

Abstract

High doses of micafungin are advocated in neonates with systemic candidiasis but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, 3 with meningitis, were treated for at least 14 days with 8 to 15 mg/kg/day of intravenous micafungin. Plasma concentrations (4 measurements) were determined after the third dose and cerebrospinal-fluid (CSF) concentrations were also obtained in three patients. Population PK analyses were used to identify the optimal model and further validated using external data (n=5). The safety of micafungin was assessed through liver and kidney function biomarkers. The mean (standard deviation) age and weight at administration was 2.33 (1.98) months and 3.24 (1.61) kg, respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase ratio. The CSF was sampled in three patients with observed concentrations between 0.80-1.80 mg/L. The model predicted mean (SD) micafungin AUC24 values is 336 (165) h•mg/L with a 10 mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection but five had neurologic impairments. Among transaminases, alkaline phosphatase measurements were significantly higher post-treatment with a geometric mean ratio [90% confidence interval] of 1.17 [1.01, 1.37]. Furthermore, marked elevations in gamma-glutamyl transferase (GGT) was observed in three patients treated with 10-15 mg/kg/day doses and improvement in GGT was noted after dose reduction. Higher weight-based doses of micafungin are generally well tolerated in neonates and infants and achieve pharmacokinetic profiles predictive of effect.
Auriti, Cinzia; Falcone, Marco; Ronchetti, Maria Paola; Goffredo, Bianca Maria; Cairoli, Sara; Crisafulli, Rosamaria; Piersigilli, Fiammetta; Corsetti, Tiziana; Dotta, Andrea; Pai, Manjunath P.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/928207
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