A reference laboratory experience of clinically achievable voriconazole, posaconazole, and itraconazole concentrations within the bloodstream and cerebral spinal fluid.

Interest in antifungal therapeutic-drug monitoring has increased due to studies demonstrating associations between concentrations and outcomes. We reviewed the antifungal drug concentration database at our institution to gain a better understanding of achievable triazole drug levels. Antifungal concentrations were measured by high-performance liquid chromatography (HPLC), ultraperformance liquid chromatography and single-quadrupole mass spectrometry (UPLC/MS), or a bioassay. For this study, only confirmed human bloodstream (serum or plasma) and cerebral spinal fluid (CSF) concentrations of voriconazole, posaconazole, and itraconazole were analyzed. The largest numbers of bloodstream and CSF samples were found for voriconazole (14,370 and 173, respectively). Voriconazole bloodstream concentrations within the range of 1 to 5.5 µg/ml represented 50.6% of samples. Levels below the lower limit of quantification (0.2 µg/ml) were observed in 14.6% of samples, and 10.4% of samples had levels of ≥5.5 µg/ml. CSF voriconazole levels ranged from undetectable to 15.3 µg/ml and were <0.2 µg/ml in 11% of samples. Posaconazole bloodstream concentrations were ≥0.7 and ≥1.25 µg/ml in 41.6% and 18.9% of samples, respectively. Posaconazole was detected in only 4 of 22 CSF samples (undetectable to 0.56 µg/ml). Itraconazole levels, as measured by UPLC/MS, were ≥0.5 µg/ml in 43.3% and were undetectable in 33.9% of bloodstream samples. In contrast, when measured by a bioassay, itraconazole/hydroxyitraconazole bloodstream concentrations were ≥1.0 µg/ml in 72.9% of samples and were undetectable in 18% of samples. These results indicate that there is marked variability in bloodstream concentrations achieved with these three azoles. In addition, many levels within the bloodstream for each azole and for voriconazole and posaconazole in the CSF were undetectable or below thresholds associated with efficacy.

Steady-state plasma concentrations of itraconazole after oral administration in Kemp's ridley sea turtles, Lepidochelys kempi.

Pharmacokinetic studies of antifungal agents in reptiles are uncommon. Itraconazole, which has been used prophylactically in juvenile sea turtles suffering from hypothermia (cold stunning) on a regular basis, was evaluated for steady-state plasma concentrations. Five Kemp's ridley sea turtles (Lepidochelys kempi) receiving itraconazole at several dosages in a rehabilitation program had blood collected within 24 hr to estimate dosing frequency. Subsequently, serial blood samples of Kemp's ridley sea turtles that were given itraconazole at several dosages for 30 days to treat cold stunning were collected at various intervals to evaluate itraconazole plasma concentrations. Tissue samples were collected from one Kemp's ridley that died during rehabilitation. Plasma concentrations of itraconazole (and of hydroxyitraconazole [OH-ITRA], one of its major bioactive metabolites) were determined using a modified, validated reverse-phase high-performance liquid chromatography technique. Itraconazole concentrations in tissues were determined by bioassay to be far greater than the plasma concentrations measured in any of the turtles. At a 15-mg/kg dosage, the half-life (t1/2) was 75 hr for itraconazole and 55 hr for OH-ITRA. All dosages produced adequate concentrations in some turtles, but consistent therapeutic concentrations were produced only at 15 mg/kg q72hr and 5 mg/kg s.i.d., with the latter producing the highest plasma concentrations.

Development and validation of a high-performance liquid chromatography assay for voriconazole.

An analytical method for the determination of voriconazole (UK-109,496; Pfizer) in plasma was developed and validated. The method utilizes solid-phase extraction technology and high-performance liquid chromatography. The lower limit of quantitation is 0.2 microg/ml, and the range of linearity tested was 0.2 to 10 microg/ml.

A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution.

To determine the effect of omeprazole on peak serum concentrations (C(max)) of itraconazole oral solution (IOS), we carried out a randomized, open-label, prospective, crossover study. Fifteen healthy, non-pregnant adults received a single dose of IOS 400 mg on two occasions, at least 7 days apart, with omeprazole 40 mg nightly for 7 days before either IOS dose 1 or 2. C(max), time to C(max) (T(max)) and AUC(0-8) were determined for itraconazole and its active metabolite, hydroxyitraconazole, for each dose and compared. Omeprazole did not significantly affect the C(max), T(max) or AUC(0-8) of itraconazole or hydroxyitraconazole when administered as IOS.