Review
Posaconazole: a broad-spectrum triazole antifungal

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Summary

Posaconazale is a new triazole drug being investigated in phase III clinical trials for the treatment and prevention of invasive fungal infections. In-vitro and in-vivo studies showed that posaconazole has broad-spectrum activity against most Candida species, Cryptococcus neoformans, Aspergillus species, Fusarium species, zygomycetes, and endemic fungi. Posaconazole is given orally two to four times daily. This triazole is widely distributed in the body, metabolised mainly by the liver, and is well tolerated, even in long-term courses. Adverse events are generally mild and include headache and gastrointestinal complaints. Posaconazole has shown promising clinical efficacy against life-threatening fungal infections that are often refractory to the currently available antifungal therapies—eg, invasive aspergillosis, fusariosis, and the emerging zygomycosis.

Introduction

Invasive fungal infections have emerged as a leading cause of death in cancer patients, haemopoietic stem-cell transplant (HSCT) recipients, and other highly immunocompromised patients. The increased incidence of invasive fungal infections such as those caused by Candida species other than Candida albicans, moulds, and other emerging fungi in these patient populations is a particularly serious problem because some of these pathogens are often resistant to most of the antifungals currently available.1, 2, 3, 4, 5, 6, 7, 8

To date, only four classes of antifungal drugs have been approved for treating invasive fungal infections: the polyenes (eg, amphotericin B), the azoles (eg, ketoconazole, itraconazole, fluconazole, and voriconazole), flucytosine, and the echinocandins (eg, caspofungin).9, 10 Failure rates of these agents, including the recently introduced agents, such as voriconazole and caspofungin, are high—in the range of 60% to 70% in allogeneic HSCT recipients.2, 3, 4, 6, 9, 11, 12 In addition, increasing use of antifungal agents has led to the development of resistance to the currently available antifungals.13

The addition of posaconazole to the antifungal armamentarium is welcome because of the drug's broad spectrum and potent activity against a number of common and rare but emerging fungal pathogens, especially those refractory to standard antifungal therapy.14, 15, 16 Posaconazole is currently being investigated in phase III clinical trials for the treatment and prevention of invasive fungal infections.14, 15, 17 Posaconazole is structurally similar to the old broad-spectrum triazole itraconazole but with fluorine substituents in place of chlorine and a furan ring in place of the dioxolane ring (figure 1).18 Posaconazole inhibits fungi by blocking ergosterol synthesis through inhibition of the enzyme lanosterol 14α-demethylase (CYP51). Ergosterol depletion coupled with the accumulation of methylated sterol precursors results in inhibition of fungal cell growth, fungal cell death, or both.

Section snippets

In-vitro activity

Posaconazole's antifungal spectrum is broad and includes causative agents of invasive fungal infections such as Candida species, Aspergillus species, non-Aspergillus hyalohyphomycetes, phaeohyphomycetes, zygomycetes, and endemic fungi.5, 19, 20, 21, 22, 23

Posaconazole cross-resistance with fluconazole, itraconazole, or both, has been shown in some candida isolates,21, 22, 24, 25 and this resistance appears to be Candida species specific. For example, cross-resistance with posaconazole and

Activity against yeasts

The in-vivo data regarding posaconazole's activity against yeasts broadly accord with in-vitro data. For example, posaconazole has been used successfully against C albicans infection57 and C neoformans infection58 in animal models.

Activity against moulds

Posaconazole is active in vivo in experimental models of invasive aspergillosis15, 44, 46, 59, 60 and disseminated fusariosis.61

Posaconazole is effective in vivo against some species of zygomycetes. Specifically, posaconazole showed no beneficial effects against

In-vitro and in-vivo combination studies

Currently, antifungal combination therapy is a proposed strategy against invasive fungal infections in highly immunocompromised patients, especially against invasive fungal infections produced by resistant moulds.4, 12, 45

Many investigators have studied combinations of antifungal drugs in the laboratory and in animal models.70 In mice infected with C albicans, survival curves showed that the combination of posaconazole plus amphotericin B had efficacy equal to or greater than that of either

Pharmacology

Posaconazole is available for oral use in clinical trials; exposure is greater when it is administered as an oral suspension than when it is administered as a tablet.79, 80 No intravenous formulation of posaconazole has yet been used in clinical trials; this might be a disadvantage when compared with other broad-spectrum antifungal agents with intravenous formulations (eg, voriconazole).

Posaconazole is generally given at a dosage of 200 mg orally four times daily for about 7 days (loading dose)

Drug interactions

The drug interactions of posaconazole and voriconazole are compared in table 2. Since posaconazole is a substrate for the CYP450 enzymes, interactions are expected with drugs that are metabolised via CYP3A4 (table 2).10, 11, 16, 33, 43, 60, 84, 93, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112 Posaconazole may have a similar drug interaction profile as itraconazole, and a less wide interaction profile compared with voriconazole.33 The clearance of

Clinical uses

In the clinical setting, posaconazole has been used mainly as salvage therapy against a wide variety of refractory invasive fungal infections, including oropharyngeal and oesophageal candidiasis, invasive candidiasis, invasive aspergillosis, fusariosis, zygomycosis, pseudallescheriasis, endemic mycoses, mycetoma, and chromoblastomycosis (table 2, figure 2). No controlled clinical trials have been reported on the use of posaconazole for prophylaxis of invasive fungal infections. There are thus

Adverse events and toxic effects

Adverse events are reported in up to 43% of patients treated with posaconazole and are most common during the first 6 months of therapy.136 The most common adverse events seem to be gastrointestinal complaints and headaches (table 4). In recent series of patients with invasive fungal infections, posaconazole therapy was well tolerated and not associated with substantial adverse events in treatment courses lasting up to 1 year.98, 106 Drug safety and tolerability were comparable for both

Conclusions

Posaconazole is a promising broad-spectrum triazole effective in vitro and in vivo against several fungi that are highly resistant to standard antifungals. Mounting evidence highlights the role of posaconazole as salvage therapy against difficult-to-treat fungal infections such as invasive aspergillosis, fusariosis, and zygomycosis. The use of posaconazole as a prophylactic agent in patients at high risk for developing invasive fungal infections and as primary therapy for these infections needs

Search strategy and selection criteria

Information for this review was identified by searches of Medline and of the extensive files of the authors. Search terms used included “posaconazole” and the drug's original code number, “SCH 56592”. We reviewed all articles and conference abstracts published in 2000 or later.

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