Posaconazole in the treatment of selected IFIs

teaser

Richard H Drew
PharmD MS BCPS
Clinical Pharmacist (Infectious Diseases)
Duke Medical Center
Assistant Professor
Duke University School of Medicine
Durham
Professor of Pharmacy
Campbell University
Buies Creek
NC, USA
E:[email protected]

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among immunocompromised patients.(1) While an expanding armamentarium of antifungal agents are available for both prevention and treatment of infections, therapeutic usefulness of these agents may be limited (in selected cases) by spectrum of activity, available dosage forms, adverse events, drug interactions and treatment failures. Clearly, there is a need for new antifungal agents in the clinical setting. Posaconazole (SCH 56592,Noxafil®; Schering-Plough) is a new triazole antifungal agent with activity against a wide variety of yeast and moulds.

Mechanism of action
Similarly to other azoles, posaconazole ­inhibits ­cytochrome P450 (CYP)-dependent 14-alpha ­demethylase in the biosynthetic pathway of ­ergosterol, resulting in a disruption of the fungal cell membrane.(2) While azole resistance may result from upregulation of efflux pumps,(3) posaconazole is not a substrate for the efflux pumps encoded by MDR1(4) or FLU1.(5) However, it can be transported by the proteins encoded by the ATP-binding cassette (ABC) transporter genes CDR1 and CDR2.(5) Although mutations in the efflux pump ERG11 have been shown to confer resistance to other azoles, resistance to posaconazole requires multiple mutations.(6) Among Candida and Aspergillus spp resistant to other azoles, the degree of in-vitro activity of posaconazole suggests a reduced potential for cross-resistance within the class.(6–8)

In-vitro studies combining posaconazole with caspofungin against Candida glabrata(9) or Aspergillus spp,(10,11) and with flucytosine against Cryptococcus neoformans,(12) have demonstrated either synergistic or additive effects. No antagonism was noted between any of the combinations. Experimental mouse models of Cryptococcus neoformans infections have been performed.(12,13) A combination of posaconazole and flucytosine was more efficacious than either drug alone,(12) while posaconazole plus amphotericin B was more effective than either drug alone at decreasing fungal burden in the brain for a few isolates.(13)

Spectrum of activity
Using methods for in-vitro susceptibility testing for posaconazole (such as microdilution,(14) disk diffusion,(14) and E-test(15,16)), it has been reported that posaconazole has activity in vitro against a broad spectrum of both yeasts and moulds (see Table 1).When compared with fluconazole, posaconazole demonstrates increased potency in vitro against non-albicans Candida spp, including C glabrata and C krusei.(7,17) In addition, posaconazole is superior to both itraconazole and voriconazole in its in-vitro activity against Zygomycetes.(7) The minimum inhibitory concentrations (MICs) reported for ­posaconazole against Aspergillus spp are comparable to those of voriconazole or itraconazole.(7)

[[HPE28_table1_35]]

Pharmacokinetics
Posaconazole pharmacokinetic evaluations have been reported for healthy adults,(18) patients with persistent febrile neutropenia,(19) and haematopoietic stem cell transplant (HSCT) recipients.(20) Because of the absence of an intravenous formulation, the absolute bioavailability has not been determined. In healthy volunteers, posaconazole had a time to maximum concentration (T(max)) of approximately five hours and a maximum concentration (C(max)) of 4,150ng/ml after administration of 400mg twice daily for 14 days.(18) Steady state was reached by day 10.(18) Dose-proportional changes in area under the time-concentration curve (AUC) and C(max) were observed up to the saturation dose of 800mg/day in both healthy adult and patient populations.(18,19) The oral suspension of posaconazole resulted in a significantly enhanced systemic exposure relative to the tablet form.(21) Divided doses (ie, 400mg twice daily or 200mg four times daily) resulted in increased systemic exposures of 98% and 220%, respectively, compared with a single dose of 800mg.(22) In healthy subjects, posaconazole absorption was significantly improved when taken either with a high-fat meal(21) or a nutritional supplement (Boost Plus).(23)

In general, increased interpatient variability of exposure (up to 68% in HSCT recipients(20)) and lower serum concentrations (eg, 52% decreased exposure in HSCT recipients(19)) have been reported in patients when compared with data from healthy volunteers. Some of this difference may be related to the variability in food intake in a patient population. In addition, mucositis may reduce posaconazole exposure without significantly affecting the mean AUC or C(max) at steady state.(20)

Posaconazole is highly protein-bound (98%)(24) and exhibits a large volume of distribution (343–1,341 litres).(18) It has a terminal-phase half-life of 25–31 hours in healthy subjects(18) and approximately 12 hours in patients.(19) In contrast to other azoles, posaconazole is not metabolised to a significant extent and is primarily (66%) excreted unchanged in the faeces.(25) Posaconazole is not a CYP substrate(26) but is a substrate and inhibitor of P-glycoprotein.(27) It undergoes minor oxidative metabolism via uridine 5′-diphosphate (UDP) glucuronidation (phase 2 metabolism), with approximately 14% of ­posaconazole eliminated in the urine as a glucuronide conjugate.(25) Renal dysfunction and haemodialysis have no effect on the pharmacokinetic profile.(24) While mild-to-moderate liver disease does not significantly alter the metabolism of posaconazole, patients with severe hepatic failure have demonstrated a twofold rise in AUC.(28) Posaconazole inhibits hepatic isoform CYP3A4, but not 1A2, 2C8, 2C9, 2D6 or 2E1.(26) Therefore coadministration of posaconazole with drugs metabolised by CYP3A4 may result in a significant increase in exposure of the concomitant medication (see Table 2).(29–32) Drugs that can reduce posaconazole exposure (thereby decreasing its effectiveness) include ­cimetidine,(33)­rifabutin(30) and phenytoin.(31) Coadministration with these agents is not recommended unless the benefit clearly outweighs the risks.

[[HPE28_table1_35]]

Clinical efficacy
Several clinical trials have been conducted to evaluate the efficacy of posaconazole. In a multicentre, randomised trial of HIV-infected patients with oropharyngeal candidiasis (n=350), ­posaconazole was as effective as fluconazole in producing a successful clinical outcome, and was more effective in achieving a successful, sustained mycological response after treatment was stopped.(34) As salvage therapy for patients with refractory or intolerant Candida infections (n=53), posaconazole was as effective as the contemporaneous external control.(35)

The majority of the published experience with posaconazole has been for the treatment of IFIs in patients intolerant of or refractory to alternative therapies. For example, posaconazole exhibited a statistically significant improvement in the clinical outcomes of patients with refractory or intolerant Aspergillus infections when compared with an external control group (42% success vs 26%, respectively; p=0.006).(35) Posaconazole has also been evaluated as salvage therapy for zygomycosis in a multicentre compassionate use trial (n=24).(36) Successful treatment (defined as complete or partial response) was reported for 79% of patients who were refractory to standard therapy.(36)

Zygomycotic and fusarium infections can be especially problematic due to the limited number of available treatment options. In a retrospective study of 91 patients with refractory or intolerant zygomycosis, high overall success and survival rates were noted in patients receiving posaconazole.(37) A complete or partial response occurred in 60% of patients after 12 weeks of treatment and 21% of patients were reported as having stable disease.(37) Fusarium species are an increasing cause of IFI, and are especially prevalent in patients with haematological malignancies.(38) In a retrospective analysis, 21 patients with invasive fusariosis were evaluated for response to posaconazole.(38) A successful outcome was recorded for 48% of the patients, with the highest response rate noted in the subset of patients who had ­recovered from neutropenia. Mycetoma and chromoblastomycosis are chronic infections which frequently require surgical treatments.(39) In an open-label study of 13 patients, successful outcomes were obtained in four out of seven of the mycetoma cases and in five out of six of the chromoblastomycoses cases.(39) Given the positive response, further long-term studies are warranted. Significant clinical improvements have also been reported in patients with disseminated coccidioidomycosis (five out of six patients)(40) and in patients with histoplasmosis (six out of seven patients).(41)

Fungal infections of the central nervous system (CNS) are most frequently encountered in immunocompromised patients. Analysis of a subset of 53 patients with CNS infections treated with ­posaconazole was taken from a multinational, open-label clinical trial.42 Infectious aetiologies included Cryptococcus spp (n=29), Aspergillus spp (n=4), Pseudallescheria boydii (n=2), Coccidioides immitis (n=1), Histoplasma ­capsulatum (n=1), Ramichloridium mackenziei (n=1) and Apophysomyces elegans plus Basidiomycetes spp (n=1). After treatment with posaconazole, ­successful outcomes were reported in 48% of patients with cryptococcal infections and 50% of patients with CNS infections due to other fungal pathogens.(42)

Because of the difficulty in treating an IFI once it is established, prophylaxis of high-risk patient populations has become an increasingly standard practice. Two randomised clinical trials have been performed to evaluate posaconazole prophylaxis in high-risk patient populations.

In the first trial, allogeneic HSCT recipients with graft versus host disease (n=600) received treatment with either posaconazole or ­fluconazole for up to 16 weeks. A significant reduction was observed in the incidence of breakthrough IFIs in the posaconazole group compared with the fluconazole group (2% vs 8%, p=0.004).(43)

In the second trial, 602 high-risk neutropenic patients with acute ­myelogenous leukaemia or myelodysplastic syndrome and who were being treated with intensive chemotherapy were randomised to receive either posaconazole or standard azoles (fluconazole or itraconazole).(44) As in the first study, posaconazole prophylaxis resulted in the development of fewer IFIs, and also conferred a significant survival benefit, with a mortality rate of 16% in the posaconazole group versus 22% in the standard azole group (p=0.048).(44)

Safety
Posaconazole has been shown to be safe and well-tolerated,(45) even in long-term use.(40,46) In healthy subjects, adverse events following posaconazole therapy were generally mild and self-limiting, occurring with an incidence rate similar to that of placebo.(45) Gastrointestinal intolerance was the principal adverse event.(45)

Overall, posaconazole demonstrated comparable tolerability when directly compared with “standard azole therapy” (ie, either fluconazole or ­itraconazole).(44) A potential for QT interval prolongation has been noted, although current observations suggest a minimal effect.(45,47) A small percentage of patients (2%) has been observed to experience an elevation in hepatic enzymes.(46)

Dosing and administration
Posaconazole is available as an oral suspension at a concentration of 40mg/ml. For treatment of IFIs, posaconazole should be administered at a dose of 400mg twice daily with a meal or nutritional supplement.(48) Patients unable to tolerate a meal or nutritional supplement may be administered 200mg four times a day.(48) No dosage adjustments appear necessary based on age,(49) genre,(49) race(50) or renal dysfunction.(24) In clinical studies, hepatically-impaired patients exhibited a trend towards higher exposure of posaconazole relative to healthy adults, but routine dose adjustments do not appear to be necessary in this population.(28) Although there is no published information on patients <8 years of age, ­posaconazole plasma concentrations were similar in patients 8–18 years of age and in adults.(51)

Approved indications
Posaconazole is approved by the European Medicines Agency (EMEA) for use in adult patients with the following conditions:

• Invasive aspergillosis in patients refractory to or intolerant of amphotericin B or itraconazole.
• Fusariosis in patients refractory to or intolerant of amphotericin B.
• Chromoblastomycosis and mycetoma in patients refractory to or intolerant of itraconazole.
• Coccidioidomycosis in patients refractory to or intolerant of amphotericin B, itraconazole or fluconazole.(48)

Conclusion
Posaconazole has been approved in Europe for use in several indications, including invasive ­aspergillosis, fusariosis, chromoblastomycosis and mycetoma in patients intolerant of or refractory to standard therapies. There are also a number of emerging applications for which posaconazole may satisfy an unmet medical need. Because of its spectrum of activity, posaconazole may be effective in other IFIs that are unresponsive to prior therapy. Posaconazole also appears to be a promising prophylactic agent in patient populations that are at high risk of ­developing an IFI.

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