Posaconazole

General information

Posaconazole is a lipophilic antifungal triazole. In vitro, it has broad-spectrum activity against opportunistic, endemic, and dermatophytic fungi, including organisms that are often resistant to existing agents, such as C. glabrata , C. krusei , A. terreus , Fusarium species, and the Zygomycetes [ , ]. A large variety of animal models of invasive fungal infections have provided consistent evidence of efficacy against these organisms in vivo.

Posaconazole was well tolerated and as effective as fluconazole 100 mg in two large randomized comparisons in HIV-infected patients with oropharyngeal candidiasis. In a salvage study in patients with a variety of invasive fungal infections, there were response rates of 44–80% in patients with aspergillosis, fusariosis, cryptococcosis, candidiasis, and pheohyphomycoses after 4–8 weeks of therapy [ , ].

Posaconazole is available as an oral suspension and achieves optimal exposure when administered in two to four divided doses given with food or a nutritional supplement. Posaconazole has a large volume of distribution, in the order of 5 l/kg, and a half-life of about 20 hours. It is not metabolized by CYP450 but is primarily excreted unchanged in the feces. It inhibits CYP3A4, but has no effects on CYP1A2, CYP2C8, CYP2C9, CYP2D6, and CYP2E1, and a limited spectrum of drug–drug interactions can therefore be expected.

Posaconazole had strong antifungal efficacy in phase II and III clinical trials in immunocompromised patients with oropharyngeal and esophageal candidiasis. It also had promising efficacy as salvage therapy in a large phase II study. In the subset of 107 patients with invasive aspergillosis, 42% had a complete or partial response at the end of treatment compared with 26% of a contemporaneous control cohort. Posaconazole appears to be as well tolerated as fluconazole and it is currently under regulatory review in the USA; it has been approved in the European Union for salvage treatment of invasive fungal infections including invasive aspergillosis [ , ].

Posaconazole has been approved in the EU for treatment of aspergillosis, fusariosis, chromoblastomycosis, and coccidioidomycosis refractory to or in patients intolerant of standard therapies; in addition, it has been approved for prophylaxis in high-risk patients with acute myeloblastic leukemia/myelodysplastic syndrome and allogeneic hemopoietic stem cell transplantation and graft-versus-host disease in both the EU and the USA. The recommended daily dosage for salvage treatment is 400 mg bd given with food; for patients who cannot take solid food, a dosage of 200 mg qds is recommended, preferably with a nutritional supplement. The dosage for prophylaxis is 200 mg tds.

Drug studies