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Pharmacology: Amphotericin is macrocyclic, polyene antifungal antibiotic produced by Streptomyces nodosus. Liposomes are closed, spherical vesicles formed from a variety of amphiphilic substances eg, phospholipids. Phospholipids arrange themselves into membrane bilayers when exposed to aqueous solutions. The lipophilic moiety of amphotericin allows the drug to be integrated into the lipid bilayer of the liposomes.
Amphotericin is fungistatic or fungicidal depending on the concentration attained in body fluids and the susceptibility of the fungus. AmBisome probably acts by binding to sterols in the fungal cell membrane, with a resulting change in membrane permeability, allowing leakage of a variety of small molecules. Mammalian cell membranes also contain sterols, and it has been suggested that the damage to human cells and fungal cells caused by amphotericin B may share common mechanisms.
Pharmacokinetics: The pharmacokinetic profile of AmBisome, based upon total plasma concentrations of amphotericin B, was determined in cancer patients with febrile neutropenia and bone marrow transplant patients who received 1-hr infusions of 1-7.5 mg/kg/day AmBisome for 3-20 days. AmBisome has a significantly different pharmacokinetic profile from that reported in the literature for conventional presentations of amphotericin B, with higher amphotericin B plasma concentrations (Cmax) and increased exposure (AUC0-24) following administration of AmBisome than conventional amphotericin B. After the 1st and last dose, the pharmacokinetic parameters of AmBisome (mean±standard deviation) ranged from: Cmax: 7.3 (±3.8) to 83.7 (±43) mcg/mL. T½: 6.3 (±2) to 10.7 (±6.4) hrs. AUC0-24: 27 (±14) to 555 (±311) mg·hr/mL. Clearance (Cl): 11 (±6) to 51 (±44) mL/hr/kg. Volume of Distribution (Vss): 0.1 (±0.07) to 0.44 (±0.27) L/kg.
Minimum and maximum pharmacokinetic values do not necessarily come from the lowest and highest doses, respectively. Following administration of AmBisome, steady state was reached quickly (generally within 4 days of dosing). AmBisome pharmacokinetics following the 1st dose appears nonlinear such that serum AmBisome concentrations are greater than proportional with increasing dose. This nonproportional dose response is believed to be due to saturation of reticuloendothelial AmBisome clearance. There was no significant drug accumulation in the plasma following repeated administration of 1-7.5 mg/kg/day. Volume of distribution on day 1 and at steady state suggests that there is extensive tissue distribution of AmBisome. After repeated administration of AmBisome the terminal elimination half-life (t½β) for AmBisome was approximately 7 hrs. The excretion of AmBisome has not been studied. The metabolic pathways of amphotericin B and AmBisome are not known. Due to the size of the liposomes there is no glomerular filtration and renal elimination of AmBisome, thus avoiding interaction of amphotericin B with the cells of the distal tubuli and reducing the potential for nephrotoxicity seen with conventional amphotericin B presentations.
Renal Impairment: The effect of renal impairment on the pharmacokinetics of AmBisome has not been formally studied.
Microbiology: Amphotericin, the antifungal component of AmBisome, shows a high order of in vitro activity against many species of fungi. Most strains of Histoplasma capsulatum, Coccidioides immitis, Candida sp, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenkii, Mucor mucedo and Aspergillus fumigatus, are inhibited by concentrations of amphotericin ranging from 0.03-1 mcg/mL in vitro. Amphotericin has minimal or no effect on bacteria and viruses.
