Dose Optimisation of Posaconazole and Therapeutic Drug Monitoring in Pediatric Patients

Abstract

Experience in the clinical use of posaconazole (PCZ) in pediatric patients is limited, and no specific dose recommendations exist. This study aimed to investigate an appropriate dosing regimen, and assess the exposure-response relationships of PCZ in children. We reviewed the medical records of inpatients aged <18 years who subjected to PCZ concentrations monitoring. Clinical data, PCZ dosing and monitoring data were collected. A total of 375 PCZ trough concentrations (C _min) from 105 pediatric patients were included. For children receiving PCZ for prophylaxis, the median doses required to achieve the therapeutic range at the ages of <6, 6-12 and >12 years were 14.80, 14.52 and 12.90 mg/kg/day, respectively (p = 0.001); and for those receiving PCZ for treatment, the median doses were 23.50, 20.96 and 15.38 mg/kg/day, respectively (p = 0.001). Among children taking PCZ for prophylaxis, 12% developed a proven or probable breakthrough IFIs; the median PCZ concentrations were significantly lower than those children with successful treatment response (0.43 versus 1.20 μg mL^-1; p < 0.001). 79.2% patients taking PCZ for treatment had a positive clinical response, and the median PCZ concentrations were significantly higher than those children with disease progression (1.06 versus 0.53 μg mL^-1; p = 0.024). No association between C _min values and hepatotoxicity was observed. Factors such as age, CRP, ALT and co-administration with proton pump inhibitors exhibited significant effects on PCZ C _min. It is necessary to adjust the dosing regimens based on PCZ C _min to individualize antifungal therapy and provide guidelines for dose adjustment in children.

Keywords: invasive fungal infections; pediatric patients; pharmacokinetics; posaconazole; therapeutic drug monitoring.

FIGURE 1

Flow chart of the study.

FIGURE 2

Distribution for PCZ Cmin at different weight-adjusted doses received. Solid and hollow red circles represent the data obtained of PCZ prophylaxis and treatment in children aged <6 years old, respectively. Solid and hollow blue square represent the data obtained of prophylaxis and treatment in children aged 6–12 years old, respectively. Solid and hollow orange triangles represent the data obtained of prophylaxis and treatment in children aged >12 years old, respectively. Two horizontal lines indicates the therapeutic range of PCZ prophylaxis and treatment (0.7 μg·mL-1 and 1.0 μg·mL-1).

FIGURE 3

Intra-and inter-patient variability of PCZ Cmin. Each boxplot represents PCZ levels (median, minimum, maximum and interquartile range) of a single child for a total of 8 children receiving 12 mg/kg/day of PCZ suspension who had five or more sample measurements.

FIGURE 4

PCZ maintenance dose required to achieve therapeutic Cmin for different age and the indication of treatment. Horizontal bars represent the median dose values for each group. y, years.

FIGURE 5

Logistic regression model showing PCZ C _min predicting the probability of successful clinical response of prophylaxis and treatment. The solid lines represent the regression fit; C _min, posaconazole average steady-state plasma concentrations.

FIGURE 6

Effect of proton pump inhibitors (PPIs) on dose-normalized PCZ C _min. The graph shows boxplots with whiskers (min to max) of dose-normalized C _min.