AmBisome Mechanism of Action

Pharmacotherapeutic group: Antimycotics for systemic use, antibiotics. ATC code: J02AA01.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Amphotericin B is a macrocyclic, polyene antifungal antibiotic produced by Streptomyces nodosus.
Liposomes are closed, spherical vesicles formed from a variety of amphiphilic substances such as 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 B is fungistatic or fungicidal depending on the concentration attained in body fluids and the susceptibility of the fungus. The drug is thought to act 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.
Paediatric population: The pharmacodynamic profile of AmBisome in paediatric patients is consistent with that described in adult patients.
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 hour infusions of 1.0 to 7.5 mg/kg/day AmBisome for 3 to 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 (C_max) and increased exposure (AUC_0-24) following administration of AmBisome than conventional amphotericin B.
After the first and last dose the pharmacokinetic parameters of AmBisome (mean ± standard deviation) ranged from: C_max: 7.3 μg/mL (±3.8) to 83.7 μg/mL (±43.0); T_½: 6.3 hr (±2.0) to 10.7 hr (±6.4); AUC_0-24: 27 μg·hr/mL (±14) to 555 μg·hr/mL (±311); Clearance (Cl): 11 mL/hr/kg (±6) to 51 mL/hr/kg (±44); Volume of distribution (Vss): 0.10 L/kg (±0.07) to 0.44 L/kg (±0.27).
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).
Absorption: AmBisome pharmacokinetics following the first dose appear non-linear such that serum AmBisome concentrations are greater than proportional with increasing dose.
This non-proportional 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 to 7.5 mg/kg/day.
Distribution: Volume of distribution on day 1 and at steady state suggests that there is extensive tissue distribution of AmBisome.
Elimination: After repeated administration of AmBisome the terminal elimination half-life (t_½β) for AmBisome was approximately 7 hours.
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 cells of the distal tubuli and reducing the potential for nephrotoxicity seen with conventional amphotericin B presentations.
Other special populations: Renal Impairment: The effect of renal impairment on the pharmacokinetics of AmBisome has not been formally studied. Data suggest that no dose adjustment is required in patients undergoing haemodialysis or filtration procedures, however, AmBisome administration should be avoided during the procedure.
Toxicology: Preclinical safety data: In repeat dose toxicity studies in dogs (1 month), rabbits (1 month) and rats (3 months) at doses equal to or, in some species, less than the clinical therapeutic doses of 1 to 3 mg/kg/day, the target organs for AmBisome toxicity were the liver and kidneys, both known target organs for amphotericin B toxicity.
AmBisome was found to be non-mutagenic in bacterial and mammalian systems.
Carcinogenicity studies have not been conducted with AmBisome.
No adverse effects on male or female reproductive function were noted in rats.
Microbiology: Amphotericin B, 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 spp., Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenkii, Mucor mucedo and Aspergillus fumigatus, are inhibited by concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/ml in vitro. Amphotericin B has minimal or no effect on bacteria and viruses.
AmBisome has been shown to be effective in animal models of visceral leishmaniasis (caused by Leishmania infantum and Leishmania donovani). In mice infected with Leishmania infantum and treated with AmBisome 3 mg/kg for 3-7 doses, all dosage regimens of AmBisome cured mice more promptly than sodium stibogluconate, and no toxicity was seen. In mice infected with Leishmania donovani, AmBisome was >5 times more effective and >25 times less toxic than amphotericin B.