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Liposomal Amphotericin B

Therapeutic Use in the Management of Fungal Infections and Visceral Leishmaniasis

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Summary

Synopsis

Incorporation of amphotericin B into small unilamellar liposomes (AmBisome® ) alters the pharmacokinetic properties of the drug, but allows it to retain significant in vitro and in vivo tactivity against fungal species, including Candida, Aspergillus and Cryptococcus, and parasites of the genus Leishmania.

Used as prophylaxis against fungal infections in immunocompromised patients, liposomal amphotericin B appeared to reduce the incidence of both fungal colonisation and proven fungal infections, but did not affect overall survival.

Empirical therapy with liposomal amphotericin B in immunocompromised adults or children with suspected fungal infections was at least as effective as therapy with conventional amphotericin B. In the largest noncomparative studies, liposomal amphotericin B produced mycological eradication in 40 and 83% of patients with proven Candida infections and 41 and 60% with proven Aspergillus infections; however, these studies included relatively few patients. Mycological eradication rates of 67 to 85% in patients with cryptococcal meningitis have been reported

Liposomal amphotericin B is an effective treatment for visceral leishmaniasis in immunocompetent adults and children, including those with severe or drug-resistant disease. The drug also produces good response rates in immunocompromised patients; however, relapse rates in these patients are high.

Liposomal amphotericin B is generally well tolerated. Few patients require discontinuation or dose reduction of the drug because of adverse events. The most frequently reported adverse events are hypokalaemia, nephrotoxicity and infusion-related reactions; however, these occur significantly less often after liposomal amphotericin B than after the conventional formulation of the drug.

The acquisition cost of liposomal amphotericin B is higher than that of conventional amphotericin B. Cost-effectiveness analyses did not clearly show an economic benefit for empirical liposomal amphotericin B antifungal therapy in adults; however, one model suggested that initial empirical therapy with the liposomal formulation in children may cost less per cure than initial therapy with the conventional formulation.

Liposomal amphotericin B appears to be an effective alternative to conventional amphotericin B in the management of immunocompromised patients with proven or suspected fungal infections. Use of the drug is facilitated by its greatly improved tolerability profile compared with conventional amphotericin B. Because of this, liposomal amphotericin should be preferred to conventional amphotericin B in the management of suspected or proven fungal infections in immunocompromised patients with pre-existing renal dysfunction, amphotericin B-induced toxicity or failure to respond to conventional amphotericin B. Liposomal amphotericin B may also be considered for first- or second-line treatment of immunocompetent patients with visceral leishmaniasis.

Pharmacodynamics

Amphotericin B is a macrocyclic polyene antibiotic which acts via inhibition of membrane function in susceptible fungal and Leishmania cells. Liposomal amphotericin B (AmBisome®) — produced by incorporation of amphotericin B into small, unilamellar liposomes — accumulates at sites of fungal infection, binding directly to fungal cells and causing cell death. Drug and liposome remain closely associated in circulation, permitting the administration of higher doses with reduced toxicity relative to conventional amphotericin B.

Liposomal amphotericin B is active in vitro and in vivo against a variety of pathogenic fungi and Leishmania species. In rodent models of Candida, Aspergillus and Cryptococcus infection, liposomal amphotericin B was administered in higher doses than the conventional drug, generally producing greater reductions in fungal burden. Survival rates were generally similar between the 2 formulations, although liposomal amphotericin B improved cure rates and survival compared with lower doses of conventional amphotericin B in some studies. When the 2 formulations were administered in identical milligram per kilogram dosages, they had similar effects on survival in infected animals, and conventional amphotericin B tended to produce a greater reduction in fungal burden. Against murine visceral leishmaniasis, liposomal amphotericin B was considerably more effective than conventional amphotericin B or meglumine antimonate, and it produced clinical improvement with significantly fewer doses than the latter agent.

Pharmacokinetics

After intravenous administration, liposomal amphotericin B achieves a higher peak serum concentration and larger area under the serum concentration-time curve than conventional amphotericin B. The drug appears to be taken up extensively by the reticuloendothelial system. High concentrations of drug are detected in liver and spleen, with lower concentrations found in brain, CSF, bone marrow, heart and lung.

The apparent mean half-life of liposomal amphotericin B is approximately 6 to 7 hours. Elimination of liposomal amphotericin B, like that of the conventional formulation, is poorly understood. No metabolites are known.

Therapeutic Use in Fungal Infections

Liposomal amphotericin B fungal prophylaxis was more effective than placebo in immunocompromised patients. The drug significantly reduced rates of invasive fungal infection in liver transplant recipients; among bone marrow transplant recipients, liposomal amphotericin B reduced the rate of fungal colonisation, but not invasive fungal infection. Overall survival was not affected.

Empirical therapy with liposomal amphotericin B in immunocompromised adults and children with suspected fungal infections was at least as effective as therapy with conventional amphotericin B in randomised studies. Evidence from noncomparative studies confirms the effectiveness of empirical liposomal amphotericin B in patients with suspected fungal infections, including patients who had experienced prior inefficacy or toxicity with conventional amphotericin B.

Limited data from noncomparative studies suggest that liposomal amphotericin B is effective against invasive Candida and Aspergillus infection and oral candidosis. However, fewer than 20 patients with each infection were evaluable in most studies. In the largest available studies, liposomal amphotericin B produced mycological eradication in 41 and 60% of patients with Aspergillus infection and 40 and 83% of patients infected by Candida spp. 67 to 85% of patients with AIDS and cryptococcal infection (primarily meningitis) who received liposomal amphotericin B achieved mycological eradication.

Therapeutic Use in Visceral Leishmaniasis

Liposomal amphotericin B is an effective treatment for visceral leishmaniasis (kala azar) in immunocompetent adults and children, clearing parasites in 100% of patients in several studies. The drug is also effective in patients with severe or pentavalent antimonial-resistant disease; however, response rates appear to be lower. In most immunocompetent patients, symptomatic improvement and objective response are detectable within 1 week of starting therapy. Liposomal amphotericin B also produces good response rates in immunocompromised patients; however, relapse rates are high. No comparative data are available.

Tolerability

Liposomal amphotericin B was generally well tolerated. The drug was discontinued because of adverse events in <5% of patients. Liposomal amphotericin B recipients experienced fewer adverse events than patients who received conventional amphotericin B. The most frequently reported adverse events in the liposomal amphotericin B group included hypokalaemia, nephrotoxicity and infusion-related fever and rigors. Increased serum liver enzymes have been noted in a substantial proportion of liposomal amphotericin B recipients. However, these patients may have been predisposed to elevations in liver enzymes by concomitant drugs or disease states; causality is unclear.

Dosage and Administration

Liposomal amphotericin B is administered as a single daily dose by slow intravenous infusion. Premedication is not required.

Used for empirical antifungal therapy in immunocompromised patients, the recommended (US) liposomal amphotericin B dosage is 3 mg/kg/day. Patients with proven systemic fungal infections should receive 3 to 5 mg/kg/day (US) or 1 to 3 mg/kg/day (UK). The optimum duration of antifungal therapy is not well defined. In neutropenic patients, treatment is generally continued until the recovery of neutrophil counts. A dosage of liposomal amphotericin B 1 mg/kg/day has been used for fungal prophylaxis after bone marrow or liver transplantation.

In immunocompetent patients with visceral leishmaniasis, liposomal amphotericin B 3 mg/kg should be administered on days 1 to 5, 14 and 21. In immunocompromised patients, the recommended dosage is 3 mg/kg/day on days 1 to 5 and 4 mg/kg/day on days 10, 17, 24, 31 and 38. Other regimens of 21 to 30 mg/kg administered over 10 to 21 days may also be appropriate. as]Pharmacoeconomic Implications of Liposomal Amphotericin B

The acquisition cost of liposomal amphotericin B is considerably higher than that of the conventional formulation. Because of this, the prophylactic use of liposomal amphotericin B may be difficult to justify. One cost-effectiveness analysis of empirical liposomal amphotericin B therapy suggested that savings associated with the reduced toxicity and improved efficacy of the liposomal formulation in immunocompromised adults with proven or suspected fungal infections were not enough to offset its increased acquisition cost compared with the conventional formulation. Another model suggested that initial empirical therapy with liposomal amphotericin B may cost less per complete cure than the conventional formulation in children, but not in adults. No pharmacoeconomic data are available for the use of liposomal amphotericin B in patients with visceral leishmaniasis.

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    Allan J. Coukell & Rex N. Brogden

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Correspondence to Allan J. Coukell.

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Various sections of the manuscript reviewed by: J.D. Berman, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Washington, D.C., USA; C. Carbon, Assistance Publique, CHU Bichat Claude Bernard, Paris, France; R.J. Hay, St John’s Institute of Dermatology, Guy’s Hospital, London, England; W. Krüger, Knochenmarktransplantation, Abteilung Onkologie/Hämatologie, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany; O. Ringdén, Department of Immunology, Microbiology, Pathology and Infectious Diseases, Huddinge University Hospital, Karolinska Institutet, Huddinge, Sweden; J. Tollemar, Departments of Transplantation Surgery and Clinical Immunology, Huddinge University Hospital, Karolinska Institutet, Huddinge, Sweden; G.G. Zhanel, Faculties of Medicine and Pharmacy, University of Manitoba, Department of Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada.

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Coukell, A.J., Brogden, R.N. Liposomal Amphotericin B. Drugs 55, 585–612 (1998). https://doi.org/10.2165/00003495-199855040-00008

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