TY - JOUR 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 DO - 10.1124/jpet.117.245449 SP - jpet.117.245449 AU - Benedicte Lelievre AU - Marie Briet AU - Charlotte Godon AU - Pierre Legras AU - Jeremie Riou AU - Patrick Vandeputte AU - Bertrand Diquet AU - Jean Philippe Bouchara Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/02/28/jpet.117.245449.abstract N2 - 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 barriers 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 were assessed in the plasma, cerebrospinal fluid (CSF), and brain, in an experimental model of cerebral scedosporiosis in rats receiving or not cyclosporine. A single dose of voriconazole (30 mg/kg, i.v.) was administrated 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 UPLC-MS/MS and HPLC-UV methods and documented up to 48 hours after administration. Pharmacokinetic parameters were estimated using a non-compartmental approach. Voriconazole pharmacokinetic profiles were similar for plasma, CSF, and the brain in all groups studied. Voriconazole Cmax and AUC0=>48h were significantly higher in the plasma than in the CSF (CSF/plasma ratio, median [range] = 0.5 [0.39-0.55] for AUC0=>48h 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 the brain voriconazole exposure. ER -