Posaconazole: clinical pharmacology and potential for management of fungal infections

Abstract

Posaconazole is a novel lipophilic antifungal triazole that inhibits cytochrome P450-dependent 14-α demethylase in the biosynthetic pathway of ergosterol. Inhibition of this enzyme leads to an accumulation of toxic 14-α methylsterols and a depletion of ergosterol, resulting in a perturbation of the function of the fungal cell membrane and blockage of cell growth and division. In vitro, posaconazole has potent and broad-spectrum activity against opportunistic, endemic and dermatophytic fungi. This activity extends to organisms that are often refractory to existing triazoles, amphotericin B or echinocandins, such as Candida glabrata, Candida krusei, Aspergillus terreus, Fusarium spp. and the Zygomycetes. A large variety of animal models of invasive fungal infections have provided consistent evidence of efficacy against these organisms in vivo, both in normal and immunocompromised animals. Posaconazole is available as an oral suspension and optimal exposure is achieved when the drug is administered in two to four divided doses along with food or a nutritional supplement. The compound has a large volume of distribution, in the order of 5 l/kg, and a half-life of approximately 20 h. Posaconazole is not metabolized to a significant extent through the cytochrome P450 enzyme system and is primarily excreted in an unchanged form in the feces. Although it is inhibitory, cytochrome P3A4 has no effect on 1A2, 2C8, 2C9, 2D6 and 2E1 isoenzymes, and therefore, a limited spectrum of drug–drug interactions can be expected. Pharmacokinetic studies in special populations revealed no necessity for dosage adjustment based on differences in age, gender, race, renal or hepatic function. Posaconazole has demonstrated strong antifungal efficacy in Phase II and III clinical trials in immunocompromised patients with oropharyngeal and esophageal candidiasis. Posaconazole also showed promising efficacy as salvage therapy in a large Phase II study including 330 patients with invasive fungal infections intolerant to or refractory to standard therapies. Posaconazole appears to be well tolerated in a manner comparable with that of fluconazole and it is currently under regulatory review in the USA and Europe for the treatment of refractory invasive fungal infections. This drug profile reviews the preclinical and clinical pharmacology of posaconazole and its potential role for prevention and treatment of invasive fungal infections.

Keywords::

• animal models
• antifungal agents
• aspergillosis
• candidiasis
• clinical trials
• in vitro susceptibility
• mycoses
• pharmacokinetics
• posaconazole
• safety
• triazoles