RT Journal Article SR Electronic T1 Impact of Infection Status and Cyclosporine on Voriconazole Pharmacokinetics in an Experimental Model of Cerebral Scedosporiosis JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 408 OP 412 DO 10.1124/jpet.117.245449 VO 365 IS 2 A1 Bénédicte Lelièvre A1 Marie Briet A1 Charlotte Godon A1 Pierre Legras A1 Jérémie Riou A1 Patrick Vandeputte A1 Bertrand Diquet A1 Jean-Philippe Bouchara YR 2018 UL http://jpet.aspetjournals.org/content/365/2/408.abstract AB Cerebral Scedosporium infections usually occur in lung transplant recipients as well as in immunocompetent patients in the context of near drowning. Voriconazole is the first-line treatment. The diffusion of voriconazole through the blood-brain barrier in the context of cerebral infection and cyclosporine administration is crucial and remains a matter of debate. To address this issue, the pharmacokinetics of voriconazole was assessed in the plasma, cerebrospinal fluid (CSF), and brain in an experimental model of cerebral scedosporiosis in rats receiving or not receiving cyclosporine. A single dose of voriconazole (30 mg/kg, i.v.) was administered to six groups of rats randomized according to the infection status and the cyclosporine dosing regimen (no cyclosporine, a single dose, or three doses; 15 mg/kg each). Voriconazole concentrations in plasma, CSF, and brain samples were quantified using ultra-performance liquid chromatography–tandem mass spectrometry and high-performance liquid chromatography UV methods and were documented up to 48 hours after administration. Pharmacokinetic parameters were estimated using a noncompartmental approach. Voriconazole pharmacokinetic profiles were similar for plasma, CSF, and brain in all groups studied. The voriconazole Cmax and area under the curve (AUC) (AUC0 ≥ 48 hours) values were significantly higher in plasma than in CSF [CSF/plasma ratio, median (range) = 0.5 (0.39–0.55) for AUC0 ≥ 48 hours and 0.47 (0.35 and 0.75) for Cmax]. Cyclosporine administration was significantly associated with an increase in voriconazole exposure in the plasma, CSF, and brain. In the plasma, but not in the brain, an interaction between the infection and cyclosporine administration reduced the positive impact of cyclosporine on voriconazole exposure. Together, these results emphasize the impact of cyclosporine on brain voriconazole exposure.