Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation

Abstract

Background: Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics; thus, standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the pharmacokinetics of fluconazole in infants on ECMO.

Methods: Infants <120 days of age received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected preoxygenator and postoxygenator around doses 1 and 2 to calculate pharmacokinetic indices and describe oxygenator extraction. A 1-compartment model was fit to the data using nonlinear regression. Surrogate pharmacodynamic targets for efficacy were evaluated.

Results: Ten infants were enrolled. After dose 1 (n = 9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg and the median exposure in the first 24 hours (area under the curve from 0 to 24 hours) was 322 h × mg/L. After multiple doses (n = 7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg and the area under the curve from 0 to 24 hours was 352 h × mg/L. After dose 1, 78% of infants achieved the prophylaxis target, whereas only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (-2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (ρ= -0.05). There were no adverse events related to fluconazole.

Conclusions: Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.

FIGURE 1

Fluconazole concentration time profiles. A. Dose 1: Plasma concentration-time profiles in young infants (n=9) after receiving first dose of intravenous fluconazole 25 mg/kg. Concentrations at time=0 hours are concentrations prior to first dose. Pharmacodynamic (PD) target for prevention of fungal infection is serum concentration > minimum inhibitory concentration (MIC) (4 mg/L) for 84 hours (50% of the dosing interval). B. Dose 2: Plasma concentration-time profiles in young infants after receiving second dose of intravenous fluconazole 25 mg/kg (n=6). Infant #7 who received treatment fluconazole (12 mg/kg daily) is not represented in this figure. Concentrations at time=0 hours are trough concentrations prior to the second dose. PD target for prevention of fungal infection is serum concentration >MIC (4 mg/L) for 50% of the dosing interval, which was 84 hours for the once-weekly 25 mg/kg dose.

FIGURE 1

Fluconazole concentration time profiles. A. Dose 1: Plasma concentration-time profiles in young infants (n=9) after receiving first dose of intravenous fluconazole 25 mg/kg. Concentrations at time=0 hours are concentrations prior to first dose. Pharmacodynamic (PD) target for prevention of fungal infection is serum concentration > minimum inhibitory concentration (MIC) (4 mg/L) for 84 hours (50% of the dosing interval). B. Dose 2: Plasma concentration-time profiles in young infants after receiving second dose of intravenous fluconazole 25 mg/kg (n=6). Infant #7 who received treatment fluconazole (12 mg/kg daily) is not represented in this figure. Concentrations at time=0 hours are trough concentrations prior to the second dose. PD target for prevention of fungal infection is serum concentration >MIC (4 mg/L) for 50% of the dosing interval, which was 84 hours for the once-weekly 25 mg/kg dose.

FIGURE 2

Median (interquartile range) fluconazole exposure in the first 24 hours (AUC_0–24) after dose 1 and multiple doses. Pharmacodynamic target for therapy is AUC_0–24 >400 h*mg/L. AUC_0–24 indicates area under the curve from 0–24 hours.