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

Abstract

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.

FIG 1

Bloodstream concentration distributions for voriconazole (A), posaconazole (B), itraconazole as measured by UPLC/MS (C), and itraconazole/hydroxyitraconazole as measured by bioassay (D). Antifungal concentrations were measured in clinical plasma or serum samples sent to our reference laboratory by validated assays.

FIG 2

Distribution of voriconazole concentrations within the cerebral spinal fluid (CSF) (A) and voriconazole bloodstream and CSF concentrations in matched clinical samples (B).

FIG 3

Voriconazole and posaconazole median bloodstream concentrations and percentages of samples above or below a certain threshold by year.