Oral Amphotericin B

Amphotericin B is an off-patent, antifungal drug of choice for systemic, life threatening human fungal infections. Systemic fungal infections continue to be a major health care problem, with more than 300,000 infections diagnosed worldwide and approximately 130,000 in the U.S. on an annual basis. Patients whose immune system is weakened by therapies for cancer, bone marrow or solid organ transplants or by the acquired immunodeficiency syndrome (AIDS) are at the greatest risk to develop these life threatening infections. Candida- and Aspergillus species as well as Cryptococcus neoformans are the most frequent fungal pathogens in these settings, although other fungal pathogens such as Histoplasma capsulatum, Blastomyces dermatidis, Coccidioides immitis and a large variety of unusual yeasts and moulds are also important and cause significant morbidity and mortality.
For the treatment of systemic fungal infections amphotericin B is currently available only in formulations that must be administered by intravenous infusion. Three lipid-based intravenous formulations on the market have reduced toxicity when compared to generic amphotericin. None of these formulations is given orally, and the cost of these lipid-based formulations is high. Due to toxicity and an inconvenient route of administration, the currently available formulations are not administered prophylactically. The use of conventional amphotericin B to treat these infections is often limited by its propensity to cause kidney damage.
The new azole-based antifungals (such as Diflucan,Nizoral, and Spranex) are less toxic than amphotericin B, and achieve systemic bioavailability following oral administration. However, unlike amphotericin B, which kills fungal cells, these azole-based drugs only stop fungal growth. In addition, treatment with azole-based antifungals can result in the development of drug resistant fungi. In contrast, treatment with amphotericin B rarely results in the emergence of drug resistant fungi.
Target Organisms
Candida: Mucosal and Systemic Candidiasis
Candida species, which can cause both mucosal and deeply invasive infections, are the predominant pathogens associated with opportunistic fungal disease. While Candida albicans is the most common cause of disseminated nosocomial fungal infection, non­albicans Candida spp. have assumed increasing importance. These organisms have become major nosocomial causes of morbidity and mortality in the immunocompromised (1), and make opportunistic fungal infections a major cause of nosocomial disease (3-4). Mucosal candidiasis is particularly common in advanced HIV-infection. Oropharyngeal candidiasis can be painful and may extend to larynx and epiglottis, causing hoarseness and impeding the patency of the airway. Esophageal candidiasis may present with acute or chronically relapsing symptoms, consisting of substernal pain, dysphagia, odynophagia. Systemic candidiasis is a more serious condition affecting the immunocompromised patient, although not as frequently with HIV-infected patients, and refers to cases where Candida is found in the bloodstream (Candida septicemia) with or without tissue invasion or to disseminated disease where single or multiple foci are sites of infection. Following its introduction in early 1990, the antifungal triazole fluconazole has been increasingly used for treatment of mucosal and deeply invasive Candida infections. However, the widespread use of fluconazole has been associated with the emergence of fluconazole-resistant Candida spp., and there is appropriate concern about whether resistance to antifungal azoles will evolve into a serious problem. As a consequence, therapy with amphotericin B has regained importance, and safe and effective formulations of this broad-spectrum and fungicidal antifungal agent are highly warranted.
Aspergillus: Invasive Aspergillosis
Invasive aspergillosis is an increasingly common and often fatal opportunistic fungal infection in patients with hematologic malignancies. Aspergillus fumigatus accounts for the vast majority of infections, while other pathogenic species include A. flavus, A. niger and A. terreus.
Leishmania: Amphotericin B Therapy for Leishmaniasis
Leishmaniasis is a parasitic disease caused by obligate intracellular protozoa belonging to the genus Leishmania. Three clinical forms are known: cutaneous leishmaniasis (localized or diffuse disease), mucocutaneous leishmaniasis and visceral leishmaniasis. The World Health Organization estimates the incidence of leishmaniasis to be as high as 2-2.5 million cases each year (cutaneous leishmaniasis: 1.5-2 million; visceral leishmaniasis: 500 000).
Amphotericin B has emerged as the therapy of choice, particularly liposomal Amphotericin B. The WHO has stated that there ‘is a clear superiority of liposomal amphotericin B over pentavalent antimonials in terms of toxicity, ease of administration and time spent in hospital'.
As opposed to the expensive, intravenously administered liposomal formulation, BDSI’s Bioral™ Amphotericin B cochleate product (CAMB) is inexpensive. Accordingly, CAMB may greatly expand the utilization of Amphotericin B for treatment of Leishmaniais, particularly in Leishmaniasis’ primary endemic areas in the developing world, where cost and route of administration are particularly critical concerns.
Oral Amphotericin B: Reducing Side Effects and Improved Therapeutic Index with Nanocochleates
Bioral™ nanocochleate technology provides the ability to deliver amphotericin B orally, while substantially reducing toxicity. By encapsulating Amphotericin B in cochleate delivery vehicles, BDSI scientists have achieved a significant reduction in the compound’s side-effects as well as an increase in the drug’s antifungal activity. Moreover, the cochleate delivery vehicle allows the oral delivery of Amphotericin B (Bioral™ Amphotericin B). BDSI scientists and collaborators are the first to demonstrate protection in an animal model against systemic, life threatening fungal infections following oral administration of amphotericin B formulations. Although other lipid-based amphotericin B formulations are currently available, none of these formulations have demonstrated effective systemic bioavailability following oral administration.
Only cochleate-formulated amphotericin B combines the following advantages:
· Stability: Amphotericin B cochleate formulations are stable over a long period of time. Amphotericin B, a sensitive drug, maintains biological activity for several months in the cochleate form. In contrast, other commercially available Amphotericin formulations need to be used immediately
· Efficacy at low doses: Amphotericin B cochleates are effective at the same doses as the free drug, whereas the AmB lipid systems require approximately five fold higher doses. Animal models of Bioral™ Amphotericin B have demonstrated substantial improvements in available intracellular levels of Amphotericin B in affected cells and pathogens, while showing low plasma levels of toxic free Amphotericin B. The cell-targeted delivery of this compound with nanocochleates allows low dosages, with increased intracellular levels for effective fungal eradication with lowered systemic side effects.
· Increased Safety: Amphotericin B cochleate formulations benefit from the same safety profile as the lipid systems. The cochleates improve the safety profile of the free drug
· Oral administration: Cochleates allow oral delivery of Amphotericin B. The formulations cure infected animals at very low doses, essentially equivalent to those used for injectable administration
· Suitable for use outside a hospital setting: Outpatient use would reduce the cost of treatment, and facilitate use in the prevention of fungal infections in immunocompromised patients