Voriconazole pharmacokinetics in liver transplant recipients

Abstract

The objective of this study was to evaluate the pharmacokinetics of voriconazole and the potential correlations between pharmacokinetic parameters and patient variables in liver transplant patients on a fixed-dose prophylactic regimen. Multiple blood samples were collected within one dosing interval from 15 patients who were initiated on a prophylactic regimen of voriconazole at 200 mg enterally (tablets) twice daily starting immediately posttransplant. Voriconazole plasma concentrations were measured using high-pressure liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis was performed to estimate pharmacokinetic parameters. The mean apparent systemic clearance over bioavailability (CL/F), apparent steady-state volume of distribution over bioavailability (Vss/F), and half-life (t1/2) were 5.8+/-5.5 liters/h, 94.5+/-54.9 liters, and 15.7+/-7.0 h, respectively. There was a good correlation between the area under the concentration-time curve from 0 h to infinity (AUC0-infinity) and trough voriconazole plasma concentrations. t1/2, maximum drug concentration in plasma (Cmax), trough level, AUC0-infinity, area under the first moment of the concentration-time curve from 0 h to infinity (AUMC0-infinity), and mean residence time from 0 h to infinity (MRT0-infinity) were significantly correlated with postoperative time. t1/2, lambda, AUC0-infinity, and CL/F were significantly correlated with indices of liver function (aspartate transaminase [AST], total bilirubin, and international normalized ratio [INR]). The Cmax, last concentration in plasma at 12 h (Clast), AUMC0-infinity, and MRT0-infinity were significantly lower in the presence of deficient CYP2C19*2 alleles. Donor characteristics had no significant correlation with any of the pharmacokinetic parameters estimated. A fixed dosing regimen of voriconazole results in a highly variable exposure of voriconazole in liver transplant patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), the voriconazole dose can be individualized based on trough concentration measurements in liver transplant patients.

FIG. 1.

(a) Plasma concentration profiles of voriconazole during one dosing interval. Large interindividual variability can be observed. Patients 1, 3, 7, and 13 had extremely atypical profiles. (b) Mean (± standard deviation) plasma concentrations of voriconazole during one dosing interval, with patients 1, 3, 7, and 13 excluded (see text).

FIG. 2.

Correlation between AUC_0-∞ and trough concentrations (C₁₂). Main figure, r² = 0.745% when AUC_0-∞ and trough concentrations are correlated for all 11 patients who had typical profiles. Inset, r² = 0.852% when AUC_0-∞ and trough concentrations are correlated for 10 patients who had typical profiles, with patient 6 omitted.

FIG. 3.

Correlation between time (hours) posttransplantation and trough plasma concentrations of voriconazole for all 11 patients who had typical profiles.