New Lipid-Associated Amphotericin Preparations
By Thomas G. Schleis, MS, RPh
A paper published at the end of 1996 summarized the information available for three lipid formulations of amphotericin B.1 The first of the three products, Abelcet (Liposome Company, Princeton, NJ), is a concentration of ribbonlike structures composed of a bilayered membrane and amphotericin B. The second product, Amphotec (Sequus Pharmaceuticals, Menlo Park, CA), is composed of disk-like structures complexed with amphotericin B. The third product, AmBisome (Nexstar, San Dimas, CA), is composed of unilamellar vesicles (liposomes) combined with amphotericin B. The first two agents are currently available in the United States, and AmBisome is expected to be released later this year.
Pharmacokinetics
Liposomes and other lipid formulations are more selectively taken up into the reticuloendothelial system and concentrated in the liver, spleen, lungs, lymph nodes, and, to some extent, bone marrow. It also appears that monocytes may ingest such particles and further help target sites of inflammation and infection. These agents are less nephrotoxic than conventional amphotericin B due to the kidney being "targeted" to a lesser degree and renal concentrations being lower. In animal studies with Abelcet, the renal concentration has been shown to be saturable, with little increases in renal concentration occurring with escalating dosing, unlike that which occurs with amphotericin B.
Abelcet, the first of these products to be released in the United States, has been studied in leishmaniasis, candidiasis, aspergillosis, coccidioidomycosis, and cryptococcosis. Although the studies varied as to design, organism, and number of patients, Abcelet, in general, was shown to be as effective as conventional amphotericin B with a lower incidence of nephrotoxicity. This appears to be true even in cases where conventional antifungal therapy (including fluconazole and itraconazole) failed or had to be discontinued due to nephrotoxicity. In fact, in patients whose serum creatinine level was greater than 2.5 mg/dL at the initiation of Abelcet therapy, there was a significant decrease in serum creatinine levels between the second and fifth weeks following initiation of Abelcet therapy was initiated. In most cases, a dose of 5 mg/kg of Abelcet was used compared to a dose of 0.6-1.0 mg/kg of conventional amphotericin B.
The second product, Amphotec (known as Amphocil in Europe), is the second lipid-based amphotericin product to be released in the United States. Although not as extensively studied as Abelcet, in an open-label, compassionate-use trial in 168 patients with documented or presumed invasive mycosis, the preliminary report suggested that Amphotec was as effective and less nephrotoxic than amphotericin B. The doses of Amphotec used in the study were variable and in the range of 0.5-6.0 mg/kg/d.
The third product, AmBisome, is expected to be released before the end of the year. It differs from the other two agents in that it is a true liposomal product and experiences a much slower rate of uptake by the reticuloendothelial system, resulting in higher peak plasma levels. Hiemenz and Walsh mention that in vitro studies suggest that AmBisome may be less effective than conventional amphotericin B against several isolates of C. albicans,1 although the correlation between in vivo and in vitro for these agents is unclear at this time. AmBisome has been studied in Europe for more than seven years in immunocompromised patients with documented or presumed invasive fungal infections. In these studies, patients were able to receive AmBisome if they failed to respond to amphotericin B, were intolerant to that therapy, or had underlying renal insufficiency. Like the other two lipid-based products, AmBisome appeared to be effective and with a lower incidence of nephrotoxicity. There was also a trial of AmBisome as prophylaxis against invasive fungal infections in bone marrow transplant patients. In a placebo-controlled trial, AmBisome (1 mg/kg/d) resulted in fewer infections in allogeneic transplant patients, but the overall duration of survival for patients was similar. Initial studies in pediatric patients also indicate that this liposomal form of amphotericin B is safe and effective in that population.
Another method of administering amphotericin B is to combine it with a fat emulsion of the type used in total parenteral nutrition. While it appears that this formulation may reduce side effects, and some studies indicate it is as efficacious as amphotericin B,2-4 there are still questions. An analysis of these mixtures demonstrates that a great deal of the amphotericin B remains undissolved and would likely be removed by filtration. Whether or not the reduction of side effects is the result of a reduced delivery of drug has not been determined. Most researchers suggest that this method of administration should be considered investigational at this time.
Benefits
Invasive fungal infections are a major cause of morbidity and mortality in immunocompromised patients. Primary candidates for infection are those patients with solid organ transplants, HIV patients, and patients undergoing chemotherapy for malignancies. Amphotericin B has been in use for more than 40 years to treat a variety of fungal infections and, fortunately, resistance has not been a serious issue. Unfortunately, dose-related side effects, renal toxicity, and electrolyte disturbances have often made its administration to patients a challenge. The new preparations have the potential to allow more patients to receive larger doses of amphotericin B therapy and more effectively transport the molecule to the site of infection while limiting its deleterious effect on the kidney.
Table
Cost comparison of Amphotericin B Agents5
Average Wholesale Agent Dosage Price/Day
Amphotericin B 50 mg $20.75
Amphotericin B/ Liposyn 10% 500 mL 50 mg $88.38
Abelcet 500 mg $866.65
Amphotec 500 mg $800.00
While these new preparations may not necessarily reduce the commonly seen side effects such as fever, rigors, and chills, they have been shown to reduce the incidence of nephrotoxicity and associated electrolyte disturbances, even at up to 10 times the commonly administered dose of amphotericin B. Interestingly, these agents appear to be effective even when amphotericin B has failedpossibly due to the fact that they can be administered at much higher doses.
Should these new preparations be used as first line agents? Probably notat least until sufficient, well-controlled comparative studies are done with an emphasis on patient outcomes. There is also a cost consideration to take into account. The daily average wholesale costs of the agents are shown in the table. Whether shorter durations of therapy and/or lower cumulative dosages are possible with these newer agents remains to be seen. However, in patients who are intolerant of or have failed to respond to conventional amphotericin B therapy, these agents are a welcomed addition to the treatment arsenal.
References
1. Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B: Recent progress and future directions. Clin Infect Dis 1996;22:S133-144.
2. Kirsch R, et al. An emulsion formulation of amphotericin B improves the therapeutic index when treating systemic murine candidiasis. J Infect Dis 1988; 158:1065-1070.
3. Chavenet PY, et al. Trial of glucose vs. fat emulsion in preparation of amphotericin for use in HIV-infected patients with candidiasis. BMJ 1992;305:921-925.
4. Moreau P, et al. Reduced renal toxicity and improved clinical tolerance of amphotericin B mixed with Intralipid compared with conventional amphotericin B in neutropenic patients. J Antimicrob Chemotherapy 1992;30:535-541.
5. Red Book. Montvale, NJ: Medical Economics Company, Inc.; 1996
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