Steady-State Pharmacokinetics of Oral Voriconazole and Its Primary Metabolite, N -Oxide Voriconazole, Pre- and Post-Autologous Peripheral Stem Cell Transplantation

Abstract

Voriconazole (VCZ) is considered first-line therapy for invasive aspergillosis and is often empirically prescribed to prevent the emergence of invasive fungal infections in patients undergoing a peripheral stem cell transplant (PSCT) (1, 2). In volunteers and patients, VCZ displays highly variable nonlinear pharmacokinetics, which are due primarily to polymorphic cytochrome P450 2C19 (CYP2C19) metabolism (3-6). Overall, the mean pharmacokinetic data of hematological-oncological patients are similar to those of healthy volunteers (7,8). After oral and intravenous administration, VCZ is extensively metabolized to inactive metabolites, including N-oxide VCZ, 4-hydroxy-VCZ, and dihydroxy-VCZ (5, 9, 10). The primary VCZ metabolite, Noxide VCZ, results from the N-oxidation of the fluoropyrimidine ring and accounts for 21% of the VCZ recovered dose (9). The formation of this metabolite is catalyzed primarily by CYP2C19 and CYP3A4 (9-12). VCZ pharmacokinetics are further influenced by the genetic polymorphisms of CYP2C19, other drugmetabolizing enzymes, and age-based differences in drug metabolism (10-17). The pharmacokinetics of VCZ have been studied, but those of N-oxide VCZ remain poorly characterized in PSCT patients. Therefore, the primary objective of this study was to characterize oral VCZ and N-oxide VCZ pharmacokinetics preand post-adult autologous PSCT.This was an open-label, single-center pharmacokinetic study of adults undergoing an autologous PSCT and receiving oral VCZ. Patients were Ͼ17 years old, medically stable, and prescribed VCZ for prophylactic antifungal therapy by their primary physician. All subjects in the study were diagnosed with multiple myeloma, were undergoing a melphalan-based autologous PSCT, and provided informed consent. Patients with clinical and laboratory evidence of veno-occlusive disease, aplastic anemia, liver disease (ChildPugh classification B or C), a history of gastrointestinal illness, or surgery that may affect drug absorption or galactose intolerance were excluded from this study. Patients with a history of anaphylaxis to VCZ or other triazole antifungal agents or who received a systemic antifungal agent within 7 days of receiving VCZ as well as other drugs that are known to be substrates of CYP2C19, CYP3A4, or CYP2C9 were excluded. All subjects received 400 mg VCZ orally every 12 h on day 1, followed by 200 mg orally every 12 h on days 2 to 17. As part of their standard immunosuppression regimen, all subjects received high-dose dexamethasone. Repeated blood sampling occurred 2 days following the loading dose (study day 3) and 6 days post-PSCT (study day 12) at predose and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, and 12.0 h after the a.m. dose. All blood samples were analyzed in singlet by PPD/Pharmaco for analysis by high-performance liquid chromatography (HPLC) and mass spectrometry according to PPD method LCMS 244 V 2.00 (18). The accuracy of data for the N-oxide VCZ assay was within the acceptable range for assay validation, but due to slow subject accrual, our sample ag...

Evaluation of sulfobutylether-β-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy

“…Therefore, no dosage adjustment is required for voriconazole in patients undergoing CVVH. The voriconazole N-oxide metabolite was readily cleared by CVVH resulting in plasma concentrations and voriconazole/voriconazole N-oxide concentration ratios similar to those previously reported in patients without kidney dysfunction [ 13 , 14 ]. The clinical implications of these findings are yet to be determined as the voriconazole N-oxide metabolite is absent of antifungal activity and has not been linked to adverse clinical effects.…”

Autoinhibitory properties of the parent but not of the N‐oxide metabolite contribute to infusion rate‐dependent voriconazole pharmacokinetics

“…Stronger CYP3A and CYP2C19 inhibition occur at steady state concentrations of both voriconazole and voriconazole N‐oxide. With voriconazole‐N‐oxide steady‐state trough plasma concentrations of 1700 ng ml –1 in the target patient population , the inhibitory effect will mostly come from the parent drug and to a much lesser extent for CYP2C19 from the N‐oxide metabolite. eCL met was reduced by about 50% compared to baseline in the 100 mg 4 h –1 group, while we recently observed that 50 mg IV voriconazole does not alter oral midazolam clearance .…”

Application of Modified Michaelis – Menten Equations for Determination of Enzyme Inducing and Inhibiting Drugs

“…However metabolism of voriconazole could be autoaccelerated and controlled by cimetidine (Moriyama et al, 2009). Metabolism of N-oxide voriconazole differs pre and post treatment (Amsden et al, 2013). The terminal half-life is relevant to multiple dosing regimens as it controls degree of drug accumulation, concentration, fluctuations and time taken to reach equilibrium.…”