title: 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.
authors.affiliation: University of Pittsburgh, Medical Center, Pittsburgh, PA 15232, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Johnson
authors.forename: Kelong
authors.identifier: 0000-0001-8010-9898
authors.initials: K
authors.lastname: Han
authors.forename: B
authors.initials: B
authors.lastname: Capitano
authors.forename: D
authors.initials: D
authors.lastname: Blisard
authors.forename: S
authors.initials: S
authors.lastname: Husain
authors.forename: P K
authors.initials: PK
authors.lastname: Linden
authors.forename: A
authors.initials: A
authors.lastname: Marcos
authors.forename: E J
authors.initials: EJ
authors.lastname: Kwak
authors.forename: B
authors.initials: B
authors.lastname: Potoski
authors.forename: D L
authors.initials: DL
authors.lastname: Paterson
authors.forename: M
authors.initials: M
authors.lastname: Romkes
authors.forename: R
authors.initials: R
authors.lastname: Venkataramanan
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001228:Aspergillosis / Q000517:prevention & control; D005260:Female; D005838:Genotype; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014230:Triazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole