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Pharmacotherapeutic group: Antimycotics for systemic use, antibiotics. ATC code: J02AA01.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamics 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.
Microbiology: Amphotericin B, the antifungal component of Amphotericin B Liposome for Injection, 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.
Amphotericin B Liposome for Injection has been reported 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 Amphotericin B Liposome for Injection 3 mg/kg for 3-7 doses, all dosage regimens of Amphotericin B Liposome for Injection cured mice more promptly than sodium stibogluconate, and no toxicity was reported. In mice infected with Leishmania donovani, Amphotericin B Liposome for Injection was >5 times more effective and >25 times less toxic than amphotericin B.
Pediatric population: The pharmacodynamics profile of Amphotericin B Liposome for Injection in paediatric patients is consistent with that described in adult patients.
Pharmacokinetics: The pharmacokinetic profile of Amphotericin B Liposome for Injection, 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 Amphotericin B Liposome for Injection for 3 to 20 days. Amphotericin B Liposome for Injection 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 Amphotericin B Liposome for Injection than conventional amphotericin B.
After the first and last dose the pharmacokinetic parameters of Amphotericin B Liposome for Injection (mean ± standard deviation) ranged from: Cmax: 7.3 μg/ml (±3.8) to 83.7 μg/ml (±43.0).
T½: 6.3 hr (±2.0) to 10.7 hr (±6.4).
AUC0-24: 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 Amphotericin B Liposome for Injection steady state was reached quickly (generally within 4 days of dosing).
Absorption: Amphotericin B Liposome for Injection pharmacokinetics following the first dose appear non-linear such that serum Amphotericin B Liposome for Injection concentrations are greater than proportional with increasing dose.
This non-proportional dose response is believed to be due to saturation of reticuloendothelial Amphotericin B Liposome for Injection 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 Amphotericin B Liposome for Injection.
Elimination: After repeated administration of Amphotericin B Liposome for Injection the terminal elimination half/life (t½β) for Amphotericin B Liposome for Injection was approximately 7 hours.
The excretion of Amphotericin B Liposome for Injection has not been reported. The metabolic pathways of amphotericin B and Amphotericin B Liposome for Injection are not known.
Due to the size of the liposomes there is no glomerular filtration and renal elimination of Amphotericin B Liposome for Injection, 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 Amphotericin B Liposome for Injection has not been formally reported. Data suggest that no dose adjustment is required in patients undergoing haemodialysis or filtration procedures, however, Amphotericin B Liposome for Injection administration should be avoided during the procedure.
Toxicology: Preclinical safety data: In reported 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 Amphotericin B Liposome for Injection toxicity were the liver and kidneys, both known target organs for amphotericin B toxicity.
Amphotericin B Liposome for Injection was reported to be found to be non-mutagenic in bacterial and mammalian systems.
Carcinogenicity studies have not been reported with Amphotericin B Liposome for Injection.
No adverse effects on male or female reproductive function were reported in rats.
