Developmental changes of fluconazole clearance in neonates and infants in relation to ontogeny of glomerular filtration rate: literature review and data analysis

BACKGROUND: Fluconazole is frequently prescribed for the treatment of systemic fungal infection in neonates and infants. At present, prediction of fluconazole doses according to developmental changes in fluconazole clearance is not being done in these patients. We aimed to formulate a developmental model of fluconazole clearance taking into account the ontogeny of renal function, since the drug is largely eliminated renally. METHODS: We systematically retrieved the data of fluconazole pharmacokinetics and renal function in children and adults from databases (MEDLINE and Japan Medical Abstracts Society). Datasets were retrieved from individual children or groups from 9 studies comprising 55 neonates or infants at postmenstrual age (PMA) 27–58 weeks. Datasets were retrieved from 5 studies comprising 60 children and from 13 studies comprising 152 adults. Datasets of glomerular filtration rate (GFR) for individual pediatric subjects were retrieved from 4 studies comprising 187 neonates or infants. RESULTS: Fluconazole clearance normalized to body surface area (BSA) (CL(BSA)) in neonates was 1/3 to 1/4 of adult values, but CL(BSA) increased rapidly during the neonatal and infantile periods and attained near adult values at PMA 60 weeks. A significant correlation between CL(BSA) and PMA was observed in neonates and infants: CL(BSA) (mL/min/m(2)) = 0.26・ PMA (weeks) – 4.9 (r = 0.68, p < 0.001). In addition, the developmental time course of GFR normalized to BSA (GFR(BSA)) was fitted well to a sigmoidal model with the maximum GFR(BSA) of 149 mL/min/1.73m(2), PMA associated with 50% of GFR(BSA,max) (PMA(50)) of 54 weeks, and the Hill coefficient of 3.7. A significant correlation between fluconazole clearance and GFR was found in neonates and infants: CL (mL/min) = 0.34・GFR (mL/min) – 0.53 (r = 0.84, p < 0.001). Assuming that plasma drug concentrations required for treating fungal infection are comparable between children and adults, fluconazole doses for pediatric patients with given PMAs may be predicted from adult doses (such as 100 mg/day) using size-normalized clearance as a scaling factor. The predicted doses for neonates and infants were largely within the ranges recommended in the prescribing information. CONCLUSIONS: The present study indicates that fluconazole doses for neonates and infants may be predicted from developmental change of systemic clearance, the ontogeny of which parallels the maturation of nephron function.