Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies

Abstract

Voriconazole is a potent triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present population pharmacokinetic analysis evaluated voriconazole plasma concentration-time data from three studies of pediatric patients of 2 to <12 years of age, incorporating a range of single or multiple intravenous (i.v.) and/or oral (p.o.) doses. An appropriate pharmacokinetic model for this patient population was created using the nonlinear mixed-effect modeling approach. The final model described voriconazole elimination by a Michaelis-Menten process and distribution by a two-compartment model. It also incorporated a statistically significant (P < 0.001) influence of the CYP2C19 genotype and of the alanine aminotransferase level on clearance. The model was used in a number of deterministic simulations (based on various fixed, mg/kg of body weight, and individually adjusted doses) aimed at finding suitable i.v. and p.o. voriconazole dosing regimens for pediatric patients. As a result, 7 mg/kg twice a day (BID) i.v. or 200 mg BID p.o., irrespective of body weight, was recommended for this patient population. At these doses, the pediatric area-under-the-curve (AUC) distribution exhibited the least overall difference from the adult AUC distribution (at dose levels used in clinical practice). Loading doses or individual dosage adjustments according to baseline covariates are not considered necessary in administering voriconazole to children.

FIG. 1.

Observed voriconazole plasma concentrations following i.v. (A) and p.o. (B) administration versus time after last dose, conditioned on the nominal study day. Day 1, all data for 0 to 48 h, corresponding to days 1 and 2, for all studies; day 4, all data for >48 to 96 h, corresponding to days 3, 4, and 5, for studies B and C only; day 8, all data for >96 to 192 h, corresponding to days 6, 7, 8, and 9, for studies B and C only; day 12, all data for >196 h, corresponding to >9 days, for study C only.

FIG. 2.

Logarithms of observed voriconazole concentrations versus population predictions split by patient weights (kg). Data for the lightest patients are shown to the lower left, and those for the heaviest patients are shown to the upper right. The weight ranges corresponding to each individual graph are indicated by the distribution bars at the top.

FIG. 3.

Cumulative distributions for voriconazole AUCs from study C following multiple dosing. AUCs were calculated for one dosing interval, using the linear trapezoidal rule (NCA analysis), or from the mixed-effect analysis (final model).

FIG. 4.

Percent deviations from the reference adult population AUC distribution (following 4 mg/kg BID i.v.) for a range of mg/kg i.v. pediatric doses.

FIG. 5.

Percent deviations from the reference adult population AUC distribution (following 200 mg BID p.o.) for a range of mg/kg (A) and fixed (B) p.o. pediatric doses.