ABSTRACT
Posaconazole (Noxafil, SCH-56592) is a triazole with a chemical structure similar to itraconazole (see Figure 157.1). The structures of both azoles contain extended piperazine-phenyl-triazole side-chains, but posaconazole is composed of a furan ring with fluorine substituted for chlorine. Like other compounds in the azole class, posaconazole inhibits the lanosterol 14-α-demethylase (CYP51), a cytochrome P450 enzyme involved in the synthesis of ergosterol. Posaconazole demonstrates potent activity against a broad range of yeasts and filamentous fungi, such as Aspergillus spp. (Castanheira et al., 2014; Diekema et al., 2003; Pfaller et al., 2013; Sabatelli et al., 2006), the majority of clinically important Mucorales (Almyroudis et al., 2007; Drogari-Apiranthitou et al., 2012; Nagappan and Deresinski, 2007; Smith et al., 2009) including Rhizopus, Mucor, Absidia, and Cunninghamella spp., dimorphic fungi (Ramani and Chaturvedi, 2007; Sabatelli et al., 2006; Wheat et al., 2006) including Penicillium (Diekema et al., 2003; Pfaller et al., 2002), Histoplasma (Sabatelli et al., 2006; Wheat et al., 2006), Blastomyces (Sabatelli et al., 2006; Sugar and Liu, 1996), and Coccidioides spp. (Ramani and Chaturvedi, 2007; Sabatelli et al., 2006), Candida spp. (Castanheira et al., 2014; Pfaller and Diekema, 2012; Pfaller et al., 2013; Pfaller et al., 2011; Sabatelli et al., 2006), including Candida albicans, Candida glabrata, Candida krusei, Candida guilliermondii, and Candida dubliniensis, and Cryptococcus spp. (Castanheira et al., 2014; Pfaller et al., 2013; Sabatelli et al., 2006). Posaconazole has Food and Drug Administration (FDA) approval for prophylaxis of invasive fungal infections in hematopoietic stem cell transplant recipients with graft-versus-host disease (GVHD) and patients with hematologic malignancies and prolonged neutropenia. It is also FDA approved for treatment of oropharyngeal candidiasis. In Europe, posaconazole is additionally approved for the following fungal infections refractory to amphotericin B and/or itraconazole: aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis. For some time, posaconazole was only available as an immediate-release oral suspension. Recently however, two new formulations, a delayed-release tablet formulation and a cyclodextrin-based intravenous formulation, were approved by the European Medicines Agency (EMA) and the FDA. These new formulations achieve higher posaconazole serum concentrations and it remains to be seen whether this may lead to an increase in the rate of adverse effects. Chemical structure of posaconazole. https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781315152110/08d8042d-9481-4a8d-8c27-9bd589f6de6b/content/fig157_1.tif" xmlns:xlink="https://www.w3.org/1999/xlink"/>
