Quantification of brain voriconazole levels in healthy adults using fluorine magnetic resonance spectroscopy

Abstract

Voriconazole is more effective for aspergillosis infections with central nervous system involvement than other antifungal agents. The clinical efficacy of voriconazole for central nervous system infections has been attributed to its ability to cross the blood-brain barrier. However, pharmacokinetic studies are limited to plasma and cerebrospinal fluid, so it remains unclear how much of the drug enters the brain. Fluorinated compounds such as voriconazole can be quantified in the brain using fluorine-19 magnetic resonance spectroscopy (MRS). Twelve healthy adult males participated in a pharmacokinetic analysis of voriconazole levels in the brain and plasma. Open-label voriconazole was dosed per clinical protocol with a loading dose of 400 mg every 12 h on day 1, followed by 200 mg every 12 h administered orally over a 3-day period. MRS was performed before and after dosing on the third day. Voriconazole levels in the brain exceeded the MIC for Aspergillus. The brain/plasma ratios were 3.0 at steady state on day 3 (predose) and 1.9 postdose. We found that voriconazole is able to penetrate the brain tissue, which can be quantified using a noninvasive MRS technique. (This study has been registered at ClinicalTrials.gov under registration no. NCT00300677.).

Figures

Fig 1

Illustration of the portion of the occipital lobe from which MRS data were collected. The brightest regions correspond to areas of maximum coil sensitivity with the major contribution from brain tissue.

Fig 2

(A) Chemical structure of voriconazole. The locations of the three fluorine sites used to obtain the peaks are circled and labeled as voriconazole A, B, and C, and the oxidation site for the N-oxide metabolite is indicated by the arrow. (B) Chemical shifts for voriconazole and metabolite peaks are shown on the spectrum of a solution in vitro of voriconazole and its nitroxy metabolite. Regions used for integration of peaks (indicated by the angle brackets [“<” and “>”] along the bottom scale) and integral curves are shown.

Fig 3

(A) Change in plasma voriconazole concentration from predose to postdose measurement. (B) Change in brain voriconazole concentration from predose to postdose measurement. The data from each subject are illustrated in a different color to show the changes in individual subjects.

Fig 4

(A) Correlation between predose brain and plasma voriconazole concentrations. (B) Correlation between postdose brain and plasma voriconazole concentrations.