2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C₃₇H₄₂F₂N₈O₄ and a molecular weight of 700.8. The structural formula is:

Figure 1: Structure of Posaconazole

The extended side chains of posaconazole provide additional points of contact with the azole target, CYP51. CYP51 is an integral membrane protein that functions as a 14- a-demethylase in the synthesis pathway of the key sterol of the fungal cell membrane, ergosterol. Inhibition of this enzyme results in decreased membrane ergosterol content and accumulation of toxic methylated intermediates, with resultant disruption of fungal cell membrane function, growth inhibition, and, in some cases, cell death. The multiple hydrophobic contacts resulting from the interaction of the extended side chain within a channel of CYP51 may result in enhanced binding affinities and may account for the preservation of activity of posaconazole against fungi with resistance to fluconazole and voriconazole resulting from mutations at the active site in proximity to the heme moiety of the demethylase.

Pharmacology:^5-6

Posaconazole is both a substrate and inhibitor of Pglycoprotein, but despite genetic polymorphisms resulting in significant variability in P-glycoprotein expression among racial groups, neither race nor ethnicity significantly affect the pharmacokinetics of posaconazole. Single-nucleotide polymorphisms in UGT that encode uridine diphosphate-glucuronotransferase may play a role, but this has not been confirmed. Dose adjustment is not required in the presence of renal or hepatic insufficiency because metabolism and renal clearance play only minor roles in posaconazole’s elimination.

Drug Interactions:^7-8

Posaconazole was given in tablet form rather than as suspension. The study found that coadministration of an antacid with posaconazole had no significant effects on its bioavailability under fasting or nonfasting conditions. Other clinical studies have shown that posaconazole does not affect the metabolism of zidovudine, lamivudine, ritonavir, or indinavir. Posaconazole also did not affect the metabolism of glipizide, but some healthy subjects experienced hypoglycemia when the combination was given. It is prudent to monitor blood glucose carefully when posaconazole is administered with glipizide.

Table 2. Drug interaction with Posaconazole

Concomitant drug	Interaction
Cyclosporin	↑ Cyclosporin concentration
Tacrolimus	↑ Tacrolimus concentration
Sirolimus	↑ Sirolimus concentration
Midazolam	↑ Midazolam concentration
Ergot alkaloids	↑ Ergot alkaloids concentration
Vinca alkaloids	↑ Vinca alkaloids concentration
Statins	↑ Statins concentration
Rifabutin	↑ Rifabutin concentration ↓ Posaconazole concentration
Phenytoin	↑ Phenytoin concentration ↓ Posaconazole concentration
Cimetidine	↓ Cimetidine concentration

↑= Increases; ↓= Decreases

In Vitro Studies:^9-10

Studies show that 82.5% of isolates of Candida glabrata were susceptible to posaconazole, whereas 90.3% were susceptible to voriconazole.

Posaconazole was less active than voriconazole against Scedosporium isolates in 2 studies. In vitro data on posaconazole against Zygomycetes are summarized in table 5. Barchiesi et al. demonstrated fungicidal activity of posaconazole (minimum fungicidal concentration90, 1 mg/mL) against dermatophytes.

POSACONAZOLE IN THE TREATMENT OF CENTRAL NERVOUS SYSTEM FUNGAL INFECTIONS:^11-13

A multinational, multicentre, open-label clinical trial was conducted to evaluate the safety and efficacy of posaconazole, an extended-spectrum triazole antifungal agent, in subjects with invasive fungal infections who had refractory disease or who were intolerant of standard antifungal therapy.

Of the 330 subjects who enrolled in the study with refractory disease and underlying HIV infection, 53 had infections of the CNS, of which 39 were considered evaluable for efficacy.

Table 3. Comparison of in vitro activity of Posaconazole, Voriconazole. Itraconazole and Fluconazole against Candida species.

Candida species	No. of isolates	Posaconazole		Voriconazole		Itraconazole		Fluconazole
Candida species	No. of isolates	MIC₅₀µg/ml	MIC₉₀ µg/ml	MIC₅₀ µg/ml	MIC₉₀ µg/ml	MIC₅₀ µg/ml	MIC₉₀ µg/ml	MIC₅₀ µg/ml	MIC₉₀ µg/ml
Candida albicans	922	0.03-0.06	0.13-0.25	0.03	006	0.03-0.06	0.05-0.5	0.25	2
Candida glabrata	533	0.5-1	1-2	0.25	1	0.5-1	1-4	8	32-128
Candida parapsilosis	430	0.03-0.12	0.06-0.13	0.03	0.06	0.12-0.13	0.12-0.25	0.5-1	1-2
Candida tropicalis	379	0.03-0.12	0.12-1	0.06	2	0.06-0.13	0.12-1	0.5	1-16
Candida krusei	101	0.25-0.5	0.5	0.5	1	0.5	0.5-1	32	>64
Candida lusitaniae	44	0.03-0.12	0.06-0.13	0.03	0.06	0.06-0.25	0.25	0.5-1	2-4

Table 4: Comparison of in vitro activity of posaconazole, itraconazole and voriconazole against Zygomycetes.

Species	No. of isolates	MIC, µg/ml
Species	No. of isolates	Posaconazole	Itraconazole	Voriconazole
Mucor species	13	05-1	1-8	32 to >64
Rhizopus species	25	0.25-1	0.5-1	8 to >64
Absidia species	15	0.03-0.06	0.06	16 to >64

Most. Twenty-nine subjects had cryptococcal infections, and 10 had infections caused by other fungal pathogens. Successful outcomes were observed in 48% subjects with cryptococcal meningitis and 50% subjects with CNS infections due to other fungal pathogens. Posaconazole was well tolerated.

The success rate of posaconazole as salvage therapy for subjects with CNS fungal infections intolerant of or refractory to standard antifungal therapy approached 50%. Alternative therapies are needed with increasing reports of breakthrough fungal disease during long-term maintenance for cryptococcal meningitis with fluconazole in patients with HIV. Posaconazole, as an oral medication, have clinical activity against fungal infections of the CNS and may provide a valuable alternative to parenteral therapy in patients in whom existing antifungal agents have failed.

POSACONAZOLE IN THE TREATMENT OF DISSEMINATED:

PHAEOHYPHOMYCOSIS DUE TO EXOPHIALA SPINIFERA:^14-15

Phaeohyphomycosis defines as a subcutaneous or systemic mycoses caused by dematiaceous fungi, which, in their parasitic form, occur as septate hyphae, spherical cells, or yeast-like elements with dark brown cell walls. Around 1100 species and 160 genera of fungi have been implicated. Exophiala spinifera, a dematiaceous fungus infrequently isolated in phaeohyphomycosis. By 1992, 6 cases of phaeohyphomycosis involving E. spinifera had been established. In recent years, several new cases of phaeohyphomycosis caused by E. jeanselmei and E. spinifera have been reported and have exhibited a variety of clinical patterns like peritonitis and systemic infections. Reports noted not only that infection due to this group of organisms is increasing, but also that species such as E. jeanselmei are exhibiting unusual manifestations.

In October 1990, a 32-year-old white woman from Argentina was found with clinical signs and symptoms consistent with disseminated phaeohyphomycosis with previous medical history of asthma and congenital renal agenesis. During the next several years, the patient experienced multiple relapses and received various antifungal therapies. In June 1999, at the age of 41 years, the patient became pregnant, and the mycosis increased in severity over the next several months. At this time, itraconazole therapy was switched with amphotericin B. Postoperatively, the patient continued to receive posaconazole therapy, with continued improvements in radiographic findings and results of clinical examinations, eliminating the need for a bone graft. By the middle of December, the skin and lymph node lesions had healed completely.

Phaeohyphomycosis comprises a wide range of clinical manifestations and has a very poor prognosis. This infection affects both immunocompromised and immunocompetent hosts. Current treatment primarily involves flucytosine in combination with amphotericin B or a triazole compound. Posaconazole is well tolerated and relapses are very less in the patients. Thus, posaconazole is having better efficacy against Phaeohyphomycosis than conventional drugs.

POSACONAZOLE IN THE TREATMENT OF MUCORMYCOSIS (ZYGOMYCOSIS) IN A HEART-KIDNEY TRANSPLANT RECIPIENT:^16-17

Mucormycosis (zygomycosis) is a fungal infection caused by Zygomycetes belonging to the order Mucorales (e.g., Absidia, Mucor, and Rhizopus species). The treatment of mucormycosis consists of a combination of high-dose amphotericin B, surgical resection, and control of predisposing conditions. The nephrotoxicity is the limits of the use of amphotericin.

In January 1999, a 56-year-old male with arterial hypertension, severe dilated cardiomyopathy, type 1 diabetes, hypercholesterolemia and fibrocystic kidney disease began ambulatory. A new course of antibiotic therapy was initiated, but the patient showed no improvement. Approximately 5 days later, the patient had a fever (temperature, 40_C) and chills, despite receiving antibacterial therapy. One week after the operation, an MRI showed cardiomegaly and loculated pleural and pericardial effusions . The transplanted kidney appeared to be healthy, and there was no intra-abdominal fluid collection. Amphotericin B deoxycholate therapy (1 mg/kg q.d.) was initiated under a presumptive diagnosis of aspergillosis. In January 2001, MRI findings prompted another thoracic operation, which showed nonpurulent mediastinitis and accumulation of a brown liquid. Samples from the mass and the external wound showed aseptate filaments with right-angle branching suggestive of a Zygomycete; corresponding cultures grew Rhizopus species. Antifungal susceptibility testing showed MICs of 0.5 mg/mL for amphotericin B, 8 mg/ mL for itraconazole, 164 mg/mL for fluconazole, and 4 mg/mL for posaconazole. Treatment with oral posaconazole (200 mg q.i.d.) was begun the next day.

After 7 days of posaconazole treatment, the patient regained consciousness and no longer exhibited altered neurological function but remained febrile (temperature, 38.5_C). After 2 weeks of posaconazole therapy, the patient’s fever had resolved, and he was hemodynamically stable but weak, without neurological abnormality. The surgical incision was clean but had not yet healed. Posaconazole was well tolerated, with no adverse effects. An echocardiogram done in February 2001 showed pericardial fluid collection, and an MRI revealed a thickened (2 mm) pericardium and honeycombed fluid accumulations over the right pleural and pericardial cavities. There was no sign of constriction, although bilateral pleural effusions were still present.

After 3 weeks of oral posaconazole treatment (4 weeks after the operation), the patient’s condition was satisfactory; he was afebrile and ambulatory, and the surgical wound was nearly completely healed. Azathioprine (25 mg q.d.) was added to the immunosuppressive regimen. By treatment week 4, the patient was discharged from the hospital.

This case shows the potential benefits of treatment with oral posaconazole for patients with mucormycosis.

POSACONAZOLE IN THE TREATMENT OF OROPHARYNGEAL CANDIDIASIS IN SUBJECTS WITH HIV/AIDS:^18-19

Oropharyngeal candidiasis is the most common opportunistic infection in persons infected with HIV. According to current Infectious Disease Society of America guidelines regarding the treatment of oropharyngeal candidiasis, topical agents, including nystatin and clotrimazole troches, can be used for initial episodes, but patients with HIV infection are prone to experience relapse. These medications are inconvenient to administer, require frequent applications, and are less effective than systemic therapies. Systemic therapy with oral fluconazole or itraconazole usually is effective for treatment of oropharyngeal candidiasis. Agents such as voriconazole, caspofungin and micafungin have shown promising activity against mucocutaneous candidiasis, but the need to administer caspofungin and micafungin intravenously limits their use. Posaconazole is an extended-spectrum triazole with potent in vitro activity against Candida species (including fluconazoleresistant strains), Aspergillus, Cryptococcus, and many pathogenic molds, including Zygomycetes. In addition, there have been anecdotal reports of successful outcomes in patients with systemic candidiasis caused by C. glabrata and Candida tropicalis who could not tolerate nor had disease refractory to other antifungal agents.

Preclinical in vitro studies have demonstrated that Candida species may be less likely to develop resistance to posaconazole than to other azoles. In C. albicans, posaconazole is a substrate of ATP-dependent efflux pumps encoded by CDR1 and CDR2 but not a substrate of major facilitator pumps encoded by MDR1 and FLU1. These observations suggest that posaconazole may have clinical activity against azole-susceptible and azole-resistant Candida species.

The primary objective of this study was to evaluate the clinical efficacy of posaconazole in the treatment of oropharyngeal candidiasis in subjects with HIV infection, using fluconazole as the active comparator. Secondary objectives included evaluating mycological efficacy, safety, and clinical relapse.

This multicenter, randomized, evaluator-blinded study of subjects with HIV infection and oropharyngeal candidiasis compared efficacy of posaconazole with that of fluconazole. Subjects received either 200 mg of posaconazole or fluconazole oral suspension on day 1, followed by 100 mg/day for 13 days. The primary study end point—clinical success (cure or improvement) on day 14—was evaluated for 329 subjects. Durability of clinical success was evaluated on day 42.

Clinical success occurred in 155 (91.7%) of 169 posaconazole recipients and in 148 (92.5%) of 160 fluconazole recipients (95% confidence interval, _6.61% to 5.04%), indicating that posaconazole was not inferior to fluconazole. Clinical relapse were less in posaconazole recipients than fluconazole recipients. Adverse events were similar between treatment arms.

Figure 2: Clinical response (cure or improvement) by treatment in the modified intent-to-treat subset of HIV-infected subjects in a trial of posaconazole (POS) versus fluconazole (FLU) for treating oropharyngeal candidiasis.

Figure 3. Mycological eradication rates by treatment in the modified intent-to-treat subset of HIV-infected subjects in a trial of posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis

The results of this study demonstrate that posaconazole was as effective as fluconazole in producing a successful clinical outcome in HIV-infected subjects with oropharyngeal candidiasis. Furthermore, posaconazole appears to be more effective than fluconazole in sustaining a successful clinical outcome and maintaining a symptom-free period after discontinuation of treatment. A similar trend was observed when the mycological outcome was assessed. Rates of mycological success were similar for the posaconazole and fluconazole arms after treatment for 7 and 14 days, but significantly more posaconazole recipients than fluconazole recipients continued to have mycological.

As expected, not all subjects who demonstrated a successful clinical response also had a successful mycological response. The lower mycological relapse rate associated with posaconazole may prove to be beneficial, because the frequency of relapse observed among HIV-infected patients has been associated with both clinical and in vitro fluconazole resistance Both posaconazole and fluconazole were generally well tolerated, and no clinically significant changes in laboratory results were observed in either treatment group. Furthermore, posaconazole was well-tolerated during long-term administration, with no unique adverse events emerging over time. Studies of healthy volunteers have shown that the safety profile of posaconazole does not appear to be influenced by age, race, or sex and that posaconazole has a low potential to prolong the QTc interval at plasma concentrations.

Thus, posaconazole may offer a beneficial alternative to other antifungal agents currently in clinical use for treating oropharyngeal candidiasis.

DISCUSSION:

Fungal infections have been emerged as a serious question. Conventional drug therapy can treat well known pathogen attacks with great efficacy. But new challenges are waiting as new strains of pathogens have been emerged that are resistant to already existing therapy. Moreover, it is difficult to treat the infections when it is found with some other conditions that can limit the use of traditional drug therapy.

Posaconazole has come up with the similar or greater efficacy and potency to the old species of pathogens. Furthermore, it is also useful in treating the new emerging pathogens where traditional therapy fails. For the strains, resistant to conventional therapy, posaconazole found effective. It has broad spectrum activity. Posaconazole was found to have a favorable safety profile during treatment of seriously ill patients with Invasive Fungal Infections. Studies show that posaconazole is more effective in treating some life threatening conditions like Phaeohyphomycosis. Current treatment primarily involves flucytosine in combination with amphotericin B or a triazole compound but Posaconazole is well tolerated and relapses are very less in the patients with Phaeohyphomycosis. For the patients with renal function impairment, posaconazole shows less adverse effects in treating Mucormycosis (zygomycosis) where conventional therapy have more adverse effects. For the HIV/AIDS patients, posaconazole found as effective as fluconazole in treating Oropharyngeal Candidiasis. But Posaconazole appears to be more effective than any other anti fungal in sustaining a successful clinical outcome and maintaining a symptom-free period in this condition.

Thus, Posaconazole is the better alternative than any other anti-fungal agent. More research can define its efficacy more clearly.

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Received on 04.02.2010 Modified on 23.02.2010

Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 694-699

Property	Posaconazole	Voriconazole	Fluconazole	itraconazole
Bioavailability	Variable	>95%	>90%	50%–75%
Protein binding	>90%	58%	11%	99%
Volume of distribution	1774 L	4.6 L/kg	0.7–0.8 L/kg	11 L/kg
Time to maximum concentration	4–5 hours	1–2 hours	2–4 hours	4–5 hours
Metabolism	Hepatic: glucuronidation to inactive metabolites	Hepatic: CYP2C19, 2C9, 3A4	Hepatic: 11% metabolized	Hepatic: CYP3A4
Elimination half-life	25–35 hours	6–24 hours (variable)	22–31 hours	35–64 hours
Elimination route	<1% excreted in urine; 66% excreted in feces	Hepatic; <2% excreted unchanged in urine	80% excreted unchanged in urine	Hepatic; <1% excreted unchanged in urine

POSACONAZOLE DRUG PROFILE: