Amphotericin B Formulations: A Comparative Review of Efficacy and Toxicity View Full Text


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Article Info

DATE

2013-06-01

AUTHORS

Richard J. Hamill

ABSTRACT

Because of the increasing prevalence and changing microbiological spectrum of invasive fungal infections, some form of amphotericin B still provides the most reliable and broad spectrum therapeutic alternative. However, the use of amphotericin B deoxycholate is accompanied by dose-limited toxicities, most importantly, infusion-related reactions and nephrotoxicity. In an attempt to improve the therapeutic index of amphotericin B, three lipid-associated formulations were developed, including amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD). The lipid composition of all three of these preparations differs considerably and contributes to substantially different pharmacokinetic parameters. ABLC is the largest of the lipid preparations. Because of its size, it is taken up rapidly by macrophages and becomes sequestered in tissues of the mononuclear phagocyte system such as the liver and spleen. Consequently, compared with the conventional formulation, it has lower circulating amphotericin B serum concentrations, reflected in a marked increase in volume of distribution and clearance. Lung levels are considerably higher than those achieved with other lipid-associated preparations. The recommended therapeutic dose of ABLC is 5 mg/kg/day. Because of its small size and negative charge, L-AmB avoids substantial recognition and uptake by the mononuclear phagocyte system. Therefore, a single dose of L-AmB results in a much higher peak plasma level (Cmax) than conventional amphotericin B deoxycholate and a much larger area under the concentration–time curve. Tissue concentrations in patients receiving L-AmB tend to be highest in the liver and spleen and much lower in kidneys and lung. Recommended therapeutic dosages are 3–6 mg/kg/day. After intravenous infusion, ABCD complexes remain largely intact and are rapidly removed from the circulation by cells of the macrophage phagocyte system. On a milligram-to-milligram basis, the Cmax achieved is lower than that attained by conventional amphotericin B, although the larger doses of ABCD that are administered produce an absolute level that is similar to amphotericin B. ABCD exhibits dose-limiting, infusion-related toxicities; consequently, the administered dosages should not exceed 3–4 mg/kg/day. The few comparative clinical trials that have been completed with the lipid-associated formulations have not demonstrated important clinical differences among these agents and amphotericin B for efficacy, although there are significant safety benefits of the lipid products. Furthermore, only one published trial has ever compared one lipid product against another for any indication. The results of these trials are particularly difficult to interpret because of major heterogeneities in study design, disease definitions, drug dosages, differences in clinical and microbiological endpoints as well as specific outcomes examined. Nevertheless, it is possible to derive some general conclusions given the available data. The most commonly studied syndrome has been empiric therapy for febrile neutropenic patients, where the lipid-associated preparations did not appear to provide a survival benefit over conventional amphotericin B deoxycholate, but did offer a significant advantage for the prevention of various breakthrough invasive fungal infections. For treatment of documented invasive fungal infections that usually involved hematological malignancy patients, no individual randomized trial has demonstrated a mortality benefit due to therapy with one of the lipid formulations. Results from meta-analyses have been contradictory, with one demonstrating a mortality benefit from all-cause mortality and one that did not demonstrate a mortality benefit. In the only published study to examine HIV-infected patients with disseminated histoplasmosis, clinical success and mortality were significantly better with L-AmB compared with amphotericin B deoxycholate; there were no differences in microbiological outcomes between treatment groups. The lipid-associated preparations were not significantly better than amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis for either clinical or microbiological outcomes that were studied. In all of the trials that specifically examined renal toxicity, the lipid-associated formulations were significantly less nephrotoxic than amphotericin B deoxycholate. Infusion-related reactions occurred less frequently with L-AmB when compared with amphotericin B deoxycholate; however, ABCD had equivalent or more frequent infusion-related reactions than conventional amphotericin B, and this resulted in the cessation of at least one clinical trial. At the present time, this particular lipid formulation is no longer commercially available. For the treatment of most invasive fungal infections, an amphotericin B lipid formulation provides a safer alternative than conventional amphotericin B, with at least equivalent efficacy. As the cost of therapy with these agents continues to decline, these drugs will likely maintain their important role in the antifungal drug armamentarium because of their efficacy and improved safety profile. More... »

PAGES

919-934

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http://scigraph.springernature.com/pub.10.1007/s40265-013-0069-4

DOI

http://dx.doi.org/10.1007/s40265-013-0069-4

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https://app.dimensions.ai/details/publication/pub.1034177761

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23729001


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94 febrile neutropenic patients
95 form
96 formulation
97 fungal infections
98 general conclusions
99 group
100 hematological malignancy patients
101 heterogeneity
102 higher peak plasma levels
103 histoplasmosis
104 important clinical differences
105 important role
106 improved safety profile
107 increase
108 index
109 indications
110 infection
111 infusion
112 infusion-related reactions
113 infusion-related toxicity
114 intravenous infusion
115 invasive fungal infections
116 kidney
117 large areas
118 large doses
119 least equivalent efficacy
120 levels
121 lipid complex
122 lipid composition
123 lipid formulations
124 lipid preparations
125 lipid products
126 lipid-associated formulations
127 liposomal amphotericin B
128 liver
129 lung
130 lung levels
131 macrophages
132 major heterogeneity
133 malignancy patients
134 marked increase
135 meningitis
136 microbiological endpoints
137 microbiological outcomes
138 microbiological spectrum
139 mononuclear phagocyte system
140 mortality
141 mortality benefit
142 negative charge
143 nephrotoxicity
144 neutropenic patients
145 one
146 outcomes
147 parameters
148 patients
149 peak plasma levels
150 phagocyte system
151 pharmacokinetic parameters
152 plasma levels
153 preparation
154 present time
155 prevalence
156 prevention
157 products
158 profile
159 reaction
160 recognition
161 renal toxicity
162 results
163 review
164 role
165 safe alternative
166 safety benefits
167 safety profile
168 serum concentrations
169 significant advantages
170 significant safety benefits
171 single dose
172 size
173 small size
174 specific outcomes
175 spectra
176 spleen
177 study
178 study design
179 substantial recognition
180 success
181 survival benefit
182 syndrome
183 system
184 therapeutic alternative
185 therapeutic dosage
186 therapeutic dose
187 therapeutic index
188 therapy
189 time
190 tissue
191 tissue concentrations
192 toxicity
193 treatment
194 treatment groups
195 treatment of AIDS
196 trials
197 uptake
198 use
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