Voriconazole pharmacokinetics and pharmacodynamics in children

Abstract

Background: Voriconazole pharmacokinetic and pharmacodynamic data are lacking in children.

Methods: Records at the Childrens Hospital Los Angeles were reviewed for children with > or =1 serum voriconazole concentration measured from 1 May 2006 through 1 June 2007. Information on demographic characteristics, dosing histories, serum concentrations, toxicity and survival, and outcomes was obtained.

Results: A total of 207 voriconazole measurements were obtained from 46 patients (age, 0.8-20.5 years). A 2-compartment Michaelis-Menten pharmacokinetic model fit the data best but explained only 80% of the observed variability. The crude mortality rate was 28%, and each trough serum voriconazole concentration <1000 ng/mL was associated with a 2.6-fold increased odds of death (95% confidence interval, 1.6-4.8; P=.002). Serum voriconazole concentrations were not associated with hepatotoxicity. Simulations predicted an intravenous dose of 7 mg/kg or an oral dose of 200 mg twice daily would achieve a trough >1000 ng/mL in most patients, but with a wide range of possible concentrations.

Conclusions: We found a pharmacodynamic association between a voriconazole trough >1000 ng/mL and survival and marked pharmacokinetic variability, particularly after enteral dosing, justifying the measurement of serum concentrations.

Figure 1

Observed vs. individual model-predicted concentrations. Solid line is the linear regression through the points; dashed line is the line of unity. Triangles are CHLA patients aged ≥12 years; squares are aged <12 years. Filled symbols are concentrations obtained after enteral dosing; open are after intravenous dosing.

Figure 2

Distribution of individual values for non-parametric model variables in the study population. Vertical dashed line is the geometric mean for patients 12 years of age and under, while dashed-dotted line is for patients over 12 years of age. P-values are for the difference between the geometric means according to age. Variable names are the same as for Table 2.

Figure 3

Simulated voriconazole concentration-time plot. Shaded bands are the indicated percentiles of 10,000 concentration-time profiles simulated from the final nonparametric model. Triangles are measured concentrations obtained in CHLA patients aged ≥12 years; squares are concentrations from CHLA patients aged <12 years. Filled symbols are concentrations obtained after enteral dosing; open are after intravenous dosing. The horizontal dashed line is the target minimum concentration of 1,000 ng/mL. Concentrations have been normalized to the median population dose, which was the same dose used for the simulations; hence, two measured concentrations appear to be at or below the assay limit of quantification (200 ng/mL).

Figure 4

Predicted voriconazole trough concentrations based on 1000 simulated patients at each age, at the licensed European dose of 200 mg enterally every 12 hours. Lines are (top to bottom) the 95^th, median, and 5^th percentiles of simulated concentrations. The target trough concentration is the horizontal reference line at 1,000 ng/mL.

Figure 5

Median simulated trough voriconazole concentration for a given enteral dose, showing the regression line with associated P-value.