Steady-state pharmacokinetics and metabolism of voriconazole in patients

Abstract

Objectives: Voriconazole exhibits non-linear pharmacokinetics in adults and is said to be mainly metabolized by CYP2C19 and CYP3A4 to voriconazole-N-oxide. The aim of this study was to obtain data on steady-state pharmacokinetics after dosing for at least 14 days in patients taking additional medication and in vivo data on metabolites other than voriconazole-N-oxide. Patients and methods: Thirty-one patients receiving voriconazole as regular therapeutic drug treatment during hospitalization participated in this prospective study. Pharmacokinetic profiles were obtained for the 12 h (dosing interval) after the first orally administered dose (400 mg) or (if possible and) after an orally administered maintenance dose (200 mg) following intake for at least 14 days (n=14 after first dose; n=23 after maintenance dose). Blood and urine samples were collected and the concentrations of voriconazole and three of its metabolites (the N-oxide, hydroxy-voriconazole and dihydroxy-voriconazole) were determined, as well as the CYP2C19 genotype of the patients. All other drugs taken by the participating patients were evaluated. Results: A high variability of exposure (AUC) after the first dosewas slightly reduced during steady-state dosing for voriconazole(82%to71%)andtheN-oxide(86%to 56%), remainedhigh for hydroxy-voriconazole(79%)andeven increased for dihydroxy-voriconazole(97%to 127%). In16 of the 22steady-state patients, trough plasmaconcentrations were<2 μg/mL. N-oxide plasma concentrations during steady state stayed almost constant. Hydroxylations of voriconazole seem to be quantitatively more important in its metabolism than N-oxidation. Conclusions: High variability in voriconazole exposure, as well as low steady-state trough plasma concentrations, suggest that the suggested steady-state dosage of 200 mg twice a day has to be increased to prevent disease progression. Therapeutic drug monitoring is probably necessary to optimize the voriconazole dose for individual patients. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.