Pharmacokinetic variability of voriconazole and N-oxide voriconazole measured as therapeutic drug monitoring.

Voriconazole (VRC), a triazole agent is extensively metabolized by CYP2C19, CYP2C9, and to a lesser extent, by CYP3A4. Few data are available regarding disposition of the main VRC metabolite (MVRC; UK121,265). The aim of this study was to investigate the pharmacokinetic variability of VRC and MVRC plasma concentrations on the basis of 115 drug monitoring samples from patients treated with VRC. Plasma concentrations of VRC and MVRC were determined by HPLC assay. During the study period, therapeutic drug monitoring (TDM) of 39 adult in- and out-patients were realized. The residual interquartile range (IQR) were 0.5-2.6 mg/l (median: 1.4 mg/l) for VRC plasma concentrations and 1.6-3.4 mg/l for MVRC (median: 2.5 mg/l). Median IQR metabolic ratio [VRC]/[MVRC] was 0.2-1.1 (median: 0.6 mg/l). VRC C(min) was <1 mg/l in 41% of cases and <0.5 mg/l in 25% of them. Patients with VRC C(min) <1 mg/l have a lower [VRC]/[MVRC] ratio than patients with VRC C(min) ≥1 mg/l (median ratio 0.1 vs. 1.0 p < 0.0001). VRC TDM is now recommended to optimize their benefit/risk ratio. In addition, measurement of MVRC in unstable patients could quickly detect patients with impaired metabolism, in cases of subtherapeutic (C(min) <1 mg/l) or toxic (C(min) >5 mg/l) VRC plasma levels.