Posaconazole: A Broad-Spectrum Triazole Antifungal Agent

Abstract

Posaconazole is a triazole antifungal agent with a spectrum of activity that includes Candida and Cryptococcus species, many molds, and some endemic fungi. Posaconazole has received US Food and Drug Administration approval for the treatment of oropharyngeal candidiasis, including infections refractory to itraconazole and/or fluconazole. It is also approved as prophylaxis for invasive Aspergillus and Candida infections in patients aged >or=13 years who are at high risk of developing these infections, in adult and adolescent hematopoietic stem cell transplant recipients with graft-versus-host disease, and in persons with hematologic malignancies and prolonged neutropenia due to chemotherapy, who are at high risk of developing these infections. Approval for additional indications is being sought. Limited clinical experience suggests efficacy for the treatment of infections due to Zygomycetes and as salvage therapy for patients with invasive aspergillosis and coccidioidomycosis. Currently available only as an oral suspension, posaconazole, which has been well tolerated, requires administration with food or a nutritional supplement to assure adequate bioavailability. Posaconazole is predominantly eliminated in the feces, where it appears as unchanged drug. Metabolism, mostly glucuronidation, plays only a minor role in its elimination, as does renal clearance; as a consequence, dose adjustment is not required in the presence of renal or hepatic insufficiency. Although not a substrate of hepatic CYP450 3A4, posaconazole inhibits this enzyme and thus has the potential for significant pharmacokinetic interactions with drugs metabolized by this isoform. Its use in combination with CYP450 substrates that prolong the QTc interval is contraindicated, as is its use with ergot alkaloids; administration of posaconazole with other substrates and/or inducers of this enzyme system requires caution. Posaconazole is both a substrate and inhibitor of P-glycoprotein. Currently, the major roles for posaconazole in clinical practice are as prophylaxis for neutropenic patients with significant risk of infection with filamentous fungi and as therapy for zygomycoses. It may also have a role in the treatment of other filamentous fungal and some yeast infections, but assessment of its overall place in antifungal therapy awaits the availability of further clinical experience.

Characterization and In Vitro Evaluation of the Complexes of Posaconazole with β- and 2,6-di-O-methyl-β-cyclodextrin

“…1a), a second-generation triazole antifungal agent, is the latest itraconazole derivative that can be administered via intravenous injection and oral suspension. POS can fight against many clinically important yeasts and fungus (1,2), including Candida sp., Aspergillus sp., Fusarium sp., zygomycetes, and other filamentous fungi (3,4). Based on its efficient and broad-spectrum antifungal performance, POS was approved for use in the United States and the European Union for the treatment of refractory invasive fungal infections and oropharyngeal candidiasis in immunocompromised patients, as well as prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients.…”

Impact of glucuronide interferences on therapeutic drug monitoring of posaconazole by tandem mass spectrometry

“…Posaconazole is intended for therapy and prophylaxis of systemic and invasive mycoses, particularly in patients with impaired immune function due to immunosuppression, AIDS, or radiation therapy w (12,13), and commentx. Posaconazole is suited especially for treatment of Candida and Aspergillus (14), but in contrast to itraconazole, it is also effective in cases with rare mycoses, such as fusarium (15) or zygomycetes (16).…”

A routine method for the quantification of the novel antimycotic drug posaconazole in plasma using liquid chromatography-tandem mass spectrometry

“…Posaconazole (SCH 56592) is a structural homologue of itraconazole; two chlorine atoms are exchanged by fluorine and one OH-function is added. The drug has recently been introduced for prophylaxis of invasive fungal infections (4,5). In two randomised phase III trials, the therapeutic efficacy of posaconazole in the prevention of fungal infection in patients with acute leukemia and graft-vs.-host-disease has been demonstrated (6,7).…”