Pharmacology: Ampholip contains the antifungal agent, amphotericin B, complexed with phospholipids. Amphotericin B is a macrocyclic, polyene, broad-spectrum antifungal antibiotic produced by Streptomyces nodosus. The lipophilic moiety of amphotericin B allows molecules of the drug to be complexed in a ribbon-like structure with the phospholipids.
Mechanism of Action: Amphotericin B, the active antifungal agent in Ampholip, may be fungistatic or fungicidal, depending on its concentration and on fungal susceptibility. Amphotericin B acts by binding to ergosterol in the fungal cell membrane causing subsequent membrane damage. As a result, cell contents leak from the fungal cell and ultimately, cell death occurs.
Microbiology: Amphotericin B is active against many fungal pathogens in vitro, including Candida sp, Cryptococcus neoformans, Aspergillus sp, Mucor sp, Sporothrix schenckii, Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum: Most strains are inhibited by amphotericin B at concentrations of 0-1 mg/mL. Amphotericin B has little or no activity against bacteria or viruses.
Pharmacokinetics: The pharmacokinetic properties of Ampholip and conventional formulation of amphotericin B containing desoxycholate are different. Pharmacokinetic studies in animals showed that, after administration of Ampholip, amphotericin B levels were higher in the liver and spleen. Amphotericin B in Ampholip was rapidly distributed to tissue. The ratio of drug concentrations in tissues to those in blood increased disproportionately with increasing dose, suggesting that elimination of the drug from the tissue was delayed. Peak blood levels of amphotericin B were lower after administration of Ampholip than after administration of equivalent amounts of conventional drug. Administration of conventional amphotericin B resulted in much lower tissue levels than did dosing with Ampholip.
The rapid clearance and large volume of distribution of Ampholip result in a relatively low AUC and are consistent with preclinical data showing high tissue concentrations. The kinetics of Ampholip are nonlinear.
Toxicology: Preclinical Safety Data: Acute toxicity studies in rodents showed that Ampholip was 10- to 20-fold less toxic than conventional amphotericin B. Multiple-dose toxicity studies in dogs lasting 2-4 weeks showed that on a mg/kg basis, Ampholip was 8- to 10-fold less nephrotoxic than conventional amphotericin B. This decreased nephrotoxicity was presumably a result of lower drug concentrations in the kidney.