Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of life

Objective To find a dose of fluconazole for very low birth weight infants during an outbreak of Candida parapsilosis . Methods Twelve premature infants (mean gestational age, 27.4 weeks; mean birth weight, 912 gm) receiving fluconazole prophylactically from the first day of life were enrolled in an open phase I‐II pharmacokinetics, safety, and tolerance trial. Up to 5 doses of 6 mg/kg were administered intravenously every 72 hours during the first 2 weeks of life. Pharmacokinetic characteristics of fluconazole were determined after the first, third, and fifth doses. Results The mean peak and trough concentrations after the 3 doses were 5.5 and 2.6 μg/ml, 12.8 and 4.3 μg/ml, and 10.0 and 2.9 μg/ml ( p = 0.0002 and p = 0.07), respectively. The mean fluconazole half‐lives were 88.6 hours ( n = 7), 67.5 hours ( n = 9), and 55.2 hours ( n = 4; p = 0.3). The mean total clearance corrected for weight (CL/kg) was 0.18 ml/min/kg ( n = 7), 0.33 ml/min/kg ( n = 7), and 0.52 ml/min/kg ( n = 4; p = 0.02), and the mean volume of distribution 1.18 L/kg ( n = 7), 1.84 L/kg ( n = 7), and 2.25 L/kg ( n = 4; p = 0.05). Weight‐corrected clearance increased with postnatal age ( r = 0.61; p = 0.007). Conclusions With the used fluconazole dose (6 mg/kg every 3 days), the mean serum peak and trough concentrations increased during the first week but decreased during the second week. After the first week we suggest a dose of 6 mg/kg every 2 days, or even daily. Clinical Pharmacology and Therapeutics (1993) 54, 269–277; doi: 10.1038/clpt.1993.147