Work

Cerebral diffusion of posaconazole in an experimental model of disseminated scedosporiosis

Year: 2025

Type: article

Abstract: Posaconazole, a broad spectrum antifungal, may be used in salvage therapy for cerebral infections caused by Scedosporium species. In this study, its pharmacokinetics was investigated in a rat model of scedosporiosis to evaluate the effect of the infection on cerebral diffusion. Posaconazole was administered to two groups of rats randomized according to the infection status. Drug levels in plasma, cerebrospinal fluid, and brain tissue were measured up to 168 h after administration, and data were analyzed using a non-compartmental approach. In addition, interleukins (IL) (IL-1β and IL-10) were quantified by ELISA, and cerebral expression of genes encoding some efflux pumps was assessed by reverse transcription-quantitative PCR. Cerebral diffusion of posaconazole and, to a lesser extent, cerebrospinal fluid exposure were significantly affected by infection. A ten-fold increase in the area under the curve and a delayed time (Tmax) to reach the maximum concentration (Cmax) were observed in the brain, along with a time lag to reach Cmax and Tmax between plasma and the brain. Infection was associated with changes in plasma pharmacokinetics, particularly at late sampling times. These findings suggest increased permeability of the blood-brain-barrier, possibly related to changes in IL or gene expression levels in the brain. Infection and the resulting inflammation should therefore be considered for therapeutic drug monitoring, especially in cases of cerebral infection. • Posaconazole may be used as salvage therapy for cerebral scedosporiosis. • The physicochemical properties of posaconazole suggest low intracerebral diffusion. • The cerebral diffusion of posaconazole is significantly increased in infected rats. • Plasma pharmacokinetics are also affected, especially at late sampling times. • Infection and inflammation should be considered for therapeutic drug monitoring.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2025.118918

Authors: Bénédicte Lelièvre, Charlotte Godon, Pierre Legras, Jérémie Riou, David Ternant, Jean-Philippe Bouchara