Bioavailability and population pharmacokinetics of voriconazole in lung transplant recipients

Abstract

This study was undertaken to characterize the pharmacokinetics and bioavailability of voriconazole in adult lung transplant patients during the early postoperative period, identify factors significantly associated with various pharmacokinetic parameters, and make recommendations for adequate dosing regimens. Thirteen lung transplant patients received two intravenous infusions (6 mg/kg, twice daily [b.i.d.]) immediately posttransplant followed by oral doses (200 mg, b.i.d.) for prophylaxis. Blood samples (9/interval) were collected during one intravenous and one oral dosing interval from each patient. Voriconazole plasma concentrations were measured by high-pressure liquid chromatography (HPLC). NONMEM was used to develop pharmacokinetic models, evaluate covariate relationships, and perform Monte Carlo simulations. There was a good correlation (R(2) = 0.98) between the area under the concentration-time curve specific for the dose evaluated (AUC(0-∞)) and trough concentrations. A two-compartment model adequately described the data. Population estimates of bioavailability, clearance, V(c), and V(p) were 45.9%, 3.45 liters/h, 54.7 liters, and 143 liters. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability (23.7%, n = 3) than non-CF patients (63.3%, n = 10). Bioavailability increased with postoperative time and reached steady levels in about 1 week. V(p) increased with body weight. Bioavailability of voriconazole is substantially lower in lung transplant patients than non-transplant subjects but significantly increases with postoperative time. CF patients exhibit significantly lower bioavailability and exposure of voriconazole and therefore need higher doses. Intravenous administration of voriconazole during the first postoperative day followed by oral doses of 200 mg or 400 mg appeared to be the optimal dosing regimen. However, voriconazole levels should be monitored, and the dose should be individualized based on trough concentrations as a good measure of drug exposure.

FIG. 1.

Plasma concentration-versus-time profiles of voriconazole. (a) Individual plasma concentration-versus-time profiles of voriconazole collected during an intravenous infusion dosing interval. (b) Mean plasma concentration-versus-time profiles of voriconazole with standard deviations (error bars) collected during an intravenous infusion dosing interval. (c) Individual plasma concentration-versus-time profiles of voriconazole collected during an oral dosing interval (one patient did not complete oral study). (d) Mean plasma concentration-versus-time profiles of voriconazole with standard deviations (error bars) collected during an oral dosing interval.

FIG. 2.

Correlation between AUC_0-∞ and voriconazole trough plasma concentrations. (a) R² = 0.83 when AUC_0-∞ and trough concentrations (C₁₂) were correlated during an intravenous infusion dosing interval (non-steady state). (Inset) R² = 0.86 when a potential outlier is omitted. Two patients had very similar C₁₂ and AUC and therefore cannot be visually separated in the figure. (b) R² = 0.98 (dashed line) and R² = 0.96 (solid line) when AUC_0-∞ was correlated with trough concentrations (C₀ [•] and C₁₂ [□], respectively) during an oral dosing interval (steady state; one patient did not complete oral study).

FIG. 3.

Goodness-of-fit of base model. Individual predictions agreed well with observations (R² = 0.96).

FIG. 4.

Change of bioavailability of voriconazole over postoperative time (POT) in patients with and without cystic fibrosis (CF). Individual parameter estimates of bioavailability obtained from model 2 were plotted against postoperative time. Bioavailability significantly, rapidly increased with POT in most of the patients, and eventually reached the maximal level within 1 week after transplant. Bioavailability was significantly lower in CF patients (dashed line) than non-CF patients (solid line). Solid gray line, population estimates from model 2.

FIG. 5.

Monte Carlo simulation. (a) Simulated voriconazole concentration-versus-time profiles during the first 2 days posttransplant in lung transplant patients with and without cystic fibrosis (CF). The median simulated voriconazole concentration in CF patients (solid line) and non-CF patients (dashed line) with 90% prediction intervals of CF patients (gray shading) and non-CF patients (hatching) is displayed. Extension of the profiles beyond 2 days posttransplant is not shown. (b) Simulated voriconazole concentration-versus-time profiles (extended until steady state was reached) in lung transplant patients receiving two doses of 2-h intravenous infusion (6 mg/kg) followed by oral doses (b.i.d.). The medians of simulated voriconazole concentration with intravenous infusion followed by oral dose of 200 mg (black line) and 400 mg (gray line) are compared. Only the 90% prediction interval for intravenous infusion followed by oral dose of 200 mg (dashed line) is displayed.