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  IN THIS Article
 ::  Abstract
 ::  Antifungal spectrum
 ::  Pharmacokinetics
 ::  Pharmacodynamics
 ::  Clinical Efficacy
 ::  Adverse Events, ...
 ::  Dosage and Admin...
 ::  References
 ::  Article Tables

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DRUG REVIEW
Year : 2010  |  Volume : 56  |  Issue : 2  |  Page : 163-167

Posaconazole


1 Department of Pediatrics, Maulana Azad Medical College & Lok Nayak Hospital, New Delhi, India
2 Department of Hematology & Oncology, All India Institute of Medical Sciences, Delhi, India

Date of Submission13-Dec-2009
Date of Decision11-Jan-2010
Date of Acceptance29-Mar-2010
Date of Web Publication8-Jul-2010

Correspondence Address:
M Bhattacharya
Department of Pediatrics, Maulana Azad Medical College & Lok Nayak Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.65281

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 :: Abstract 

Posaconazole is a novel second-generation Triazole oral antifungal agent. It is highly effective in the prophylaxis of invasive fungal infections in immunocompromised patients. It is used as a first-line agent as well as for salvage therapy in invasive fungal infections including aspergillosis, oropharyngeal and esophageal candidiasis. It has a good adverse effect profile. With the rising incidence of invasive fungal infections due to the HIV pandemic and medical advancements in transplantation and cancer therapy, these features make posaconazole a valuable addition in the family of antifungal agents.


Keywords: Posaconazole, invasive fungal infections, candidiasis, immunocompromised


How to cite this article:
Bhattacharya M, Rajeshwari K, Dhingra B. Posaconazole. J Postgrad Med 2010;56:163-7

How to cite this URL:
Bhattacharya M, Rajeshwari K, Dhingra B. Posaconazole. J Postgrad Med [serial online] 2010 [cited 2019 Aug 23];56:163-7. Available from: http://www.jpgmonline.com/text.asp?2010/56/2/163/65281


Invasive fungal infections (IFI) are a major cause of morbidity and mortality in cancer patients and hematopoietic stem cell transplant (HSCT) recipients, HIV infection and other immunosuppressed patients. Moreover, IFI caused by Candida species other than Candida albicans and other emerging fungi in these patient subgroups are often resistant to conventional antifungal agents.

At present, four classes of antifungal agents are approved for use in IFI: the polyenes (e.g. Amphotericin B), the azoles (e.g. itraconazole, fluconazole and voriconazole), flucytosine and the echinocandins (e.g. caspofungin anidula fungin). [1],[2] These agents have a high failure rate ranging from 40 to 70%. [3],[4],[5],[6] Moreover, increasing use of these agents has led to the emergence of resistance against them.

In this scenario, posaconazole, a second-generation triazole, is a welcome addition to the battery of available antifungal agents with its broad-spectrum and potent activity against common as well as rare but emerging fungal pathogens resistant to standard antifungal therapy. This article briefly reviews the clinical pharmacology, therapeutic indications, an efficacy and safety of this drug.


 :: Antifungal spectrum Top


Activity against yeasts

Posaconazole is more active than itraconazole and fluconazole against Candida species and Cryptococcus neoformans.[7],[8],[9] Its activity against Candida species is comparable to voriconazole. [9] It inhibits most fluconazole-resistant Candida (barring Candida glabrata and Candida pelliculosa) and Cryptococcus neoformans isolates. [9] Posaconazole has also exhibited fungistatic activity against Rhodotorula and Trichosporon species. [7]

Activity against moulds

Posaconazole is the most active triazole against filamentous fungi. It is 4 to 16 times more active than Amphotericin B against Aspergillus [10] It is also active against Aspergillus fumigatus resistant to itraconazole, voriconazole and Amphotericin B. [11]

Posaconazole is also active against Fusarium species. [12] It is less active than Amphotericin B, more active than voriconazole and comparable to itraconazole in zygomycosis. [13]

Activity against endemic fungi

Posaconazole shows high in vitro activity against Histoplasma capsulatum, Blastomyces dermatidis and Coccidioides and less activity against Sporothrix schenckii.[14],[15]

Resistant fungal isolates (namely Candida and Aspergillus spp.) have been reported in patients on posaconazole prophylaxis. These isolates show reduced susceptibility to other triazoles signifying cross-resistance and warrants further study. [16]

[Table 1] summarizes the differences between posaconazole and other antifungals


 :: Pharmacokinetics Top


Absorption

Due to its lipophilicity, posaconazole does not have a solubilized intravenous formulation and is administered orally. Single doses exceeding 800 mg are not fully absorbed. [17] Twelve hourly and six hourly dosing intervals increase bioavailability by 98 and 220%, respectively. [18] The suspension form has better bioavailability as compared to the tablet form. [19] Concomitant intake with high-fat and non-fat meals causes four and 2.5 times increases in bioavailability, respectively. [19] Absorption is increased with concomitant intake of proton pump inhibitors. [20]

Distribution

Posaconazole has a large volume of distribution (~1800 mL) and is highly plasma protein bound (>95%) suggesting extensive tissue distribution. [21],[22]

Metabolism and excretion

Majority of the administered dose is excreted unchanged (66%) in the feces (77%) and urine (14%) and only a small fraction is glucuronized by the UGT1A4 pathway. [22] Posaconazole has a long elimination half-life (20-66 h) and it reaches steady-state after 10 days of therapy. [21]




 :: Pharmacodynamics Top


Posaconazole has structural similarity with itraconazole but with fluorine substituents in place of chlorine and a furan ring in place of dioxolane ring. By inhibiting lanosterol 14α-demethylase (CYP51), it leads to ergosterol depletion and causes accumulation of methylated sterol precursors, which cause inhibition of fungal cell growth and fungal cell death. [23]


 :: Clinical Efficacy Top


Posaconazole has been evaluated in a number of multicenter randomized controlled trials.

Prophylaxis of IFI

Posaconazole was compared with fluconazole for the prophylaxis of IFI in patients with graft versus host disease (GVHD) on high-dose immunosuppressive therapy and was found to be equally effective in preventing all IFI and better in preventing aspergillosis. [24] In another study, in patients with acute myeloid leukemia with severe chemotherapy-induced neutropenia, posaconazole group had lower incidence of breakthrough IFI as well as aspergillosis as compared to fluconazole and itraconazole. [25]

Oropharyngeal and esophageal candidiasis

Posaconazole was non-inferior to fluconazole in HIV positive patients with esophageal candidiasis. [26] It also had high cure rates (75-85%) in the treatment of azole-resistant esophageal and/or oropharyngeal candidiasis in HIV positive patients in two different studies. [27],[28]

Invasive fungal infections

Posaconazole was used as salvage therapy in patients with invasive aspergillosis refractory or intolerant to conventional antifungals. The control group received Amphotericin B, itraconazole or a combination of both. Some external controls also received voriconazole and echinocandins as salvage therapy. Posaconazole was concluded to be an effective option in the salvage therapy of invasive aspergillosis. [29] A retrospective study to evaluate the role of posaconazole as salvage therapy versus Amphotericin B and caspofungin favored posaconazole both in response rates and mortality. [30]

Posaconazole was also found to be effective as salvage therapy in zygomycosis resistant to various formulations of Amphotericin B. [31],[32]

Other therapeutic indications under study

Despite poor penetration into the CSF, posaconazole has been found to be effective in Cryptococcal meningitis and other CNS fungal infections either alone or in combination with other antifungal agents. [33] Other therapeutic indications under study are refractory histoplasmosis, coccidioidomycosis and invasive fusariosis. [34],[35],[36]

[Table 2] lists the details of various clinical efficacy trials of posaconazole.

In light of the above studies, posaconazole is currently indicated in the prophylaxis of IFI in immunosuppressed patients and in the treatment of oropharyngeal and esophageal candidiasis including azole-refractory cases. It is also given as salvage therapy in refractory IFI such as aspergillosis, zygomycosis, fusariosis, coccidioidomycosis and histoplasmosis. [16]


 :: Adverse Events, Contraindications and Drug Interactions Top


The most commonly encountered side effects with posaconazole are nausea (5%), vomiting (4%), diarrhea (3%) and headache (1%). Cases of QT prolongation (4%) and hepatotoxicity (1%) (mild to moderate elevations of ALT, AST, ALP and serum bilirubin and/or clinical hepatitis) have been reported in clinical trials, which were reversed upon discontinuation of the drug. [21]

Posaconazole is contraindicated in patients with hypersensitivity to the drug or any other constituent of the preparation. [21]

Posaconazole is an inhibitor of hepatic CYP3A4 and hence, increases whole blood concentrations of drugs that are metabolized by this enzyme (e.g. cyclosporine, tacrolimus, sirolimus). Plasma posaconazole levels are affected by agents that induce or inhibit hepatic glucuronidation (e.g. rifabutin, phenytoin). It should be co-administered with caution with agents that are hepatic CYP3A4 substrates and prolong the QTc interval (e.g. astemizole, cisapride, halofantrine, pimozide, quinidine, terfenadine). Its use is contraindicated in the USA and EU along with statins (hepatic CYP3A4 substrates) and ergot alkaloids. When administered with vinca alkaloids, some anti-retroviral agents (ritonavir, indinavir) and calcium channel blockers (hepatic CYP3A4 substrates), dose adjustments and frequent monitoring of adverse effects and therapeutic drug monitoring are warranted. [23],[37]


 :: Dosage and Administration Top


Posaconazole is available as a suspension (40 mg/mL). The dose for prophylaxis of IFI is 200 mg thrice a day. In oropharyngeal candidiasis, the dose is 100 mg twice a day on the first day of therapy followed by 100 mg once a day for 13 days. In azole-resistant oropharyngeal candidiasis, the dose is 400 mg twice daily. The duration of therapy depends on the clinical response. For salvage therapy for refractory aspergillosis, posaconazole is given at a dose of 400 mg twice daily for a minimum of 6-12 weeks. To optimize its absorption from the gut, it should be taken with a fatty meal or liquid nutritional supplement. If this is not feasible, an alternative antifungal agent should be considered. [23],[16] An intravenous formulation is being developed. [38]

Dose adjustment in special populations

No dose adjustment is required in the geriatric or adolescent population or based on race or sex. The safety and efficacy of posaconazole have not been established in children less than 13 years of age. Hence, no dosing regime is available for this age group. [16]

Unlike other azoles, dose reduction is not necessary in renal impairment or hepatic insufficiency. The drug is not eliminated in hemodialysis. [23]

The drug belongs to pregnancy risk category C. Its excretion in breast milk is not known and is to be used only if the potential benefit to the mother outweighs the risk to the baby. [23]

Posaconazole absorption is affected by concomitant diet, gastrointestinal disorders like mucositis and diarrhea and gastric pH. It interacts with antivirals (ritonavir, efavirenz), chemotherapeutic agents (vincristine), immunosuppressants (cyclosporine, sirolimus) and benzodiazepines (midazolam). Moreover, it has been reported that average plasma posaconazole concentrations were related to the efficacy of prophylaxis. However, lack of data on a target drug concentration makes recommendation for Role of therapeutic drug monitoring difficult. TDM may be considered in failing therapy, infection of sanctuary sites, refractory organisms, gastrointestinal disorders and inability to ingest high fat meals. [37]

In conclusion, posaconazole is a new oral, broad spectrum, triazole antifungal agent. It is currently approved for prophylaxis and treatment of IFI and treatment of azole sensitive and refractory esophageal and oropharyngeal candidiasis. To prevent emergence of resistance to this valuable and novel agent it should be reserved for salvage therapy of infections resistant to conventional antifungal agents in high-risk immunocompromised patients.

 
 :: References Top

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4.Antoniadou A, Torres HA, Lewis RE, Thornby J, Bodey GP, Tarrand JP, et al. Candidemia in a tertiary care cancer center: in vitro susceptibility and its association with outcome of initial antifungal therapy. Medicine (Baltimore) 2003;82:309-21.   Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
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20.Alffenaar JW, van Assen S, van der Werf TS, Kosterink JG, Uges DR. Omeprazole significantly reduces posaconazole serum trough level. Clin Infect Dis 2009;48:839.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]  
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25.Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348-59.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]  
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27.Vazquez JA, Skiest DJ, Tissot-Dupont H, Lennox JL, Boparai N, Isaacs R. Safety and efficacy of posaconazole in the long-term treatment of azole-refractory oropharyngeal and esophageal candidiasis in patients with HIV infection. HIV Clin Trials 2007;8:86-97.  Back to cited text no. 27  [PUBMED]  [FULLTEXT]  
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36.Raad II, Hachem RY, Herbrecht R, Graybill JR, Hare R, Corcoran G, et al. Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions. Clin Infect Dis 2006;42:1398-403.  Back to cited text no. 36  [PUBMED]  [FULLTEXT]  
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    Tables

  [Table 1], [Table 2]

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