AmBisome: relationship between the pharmacokinetic characteristics acquired by liposomal formulation and safety/efficacy

Amphotericin B (AMPH-B) is a polyene antifungal agent with a superior and broad fungicidal spectrum, but its administration at a dose sufficient for treatment is difficult because of dose- and duration-dependent nephrotoxicity. To solve this dilemma, a liposomal formation of AMPH-B that achieved reduction of adverse effects while maintaining the efficacy, AmBisome® (L-AMB), was developed. In L-AMB, AMPH-B molecules are stabilized by phospholipids and cholesterol in the liposomal lipid bilayer, reducing the cytotoxicity for animal cells compared with that of the free-form AMPH-B. In addition, extravascular permeation of L-AMB is limited in normal tissue because of the liposome particle size (particle diameter: 100 nm or smaller), a high blood level is maintained and the distribution in organs, including the kidney is reduced, contributing to the improvement of the safety. On the other hand, vascular permeation increases due to inflammation and damage by fungal invasion, which increases L-AMB transfer from the circulation to lesions and its antifungal activity. Furthermore, since the parameter most closely correlated with the in vivo outcome of L-AMB is Cmax/MIC, the pharmacokinetic (PK) characteristics of L-AMB, which result in a high blood level than that for the free-form AMPH-B, is advantageous for antifungal activity. Incorporation of AMPH-B into the liposomal membrane resulted in PK characteristics of L-AMB markedly different from those of AMPH-B, and the superior efficacy and safety were achieved based on these characteristics. In this review, the relationship between the PK characteristics of L-AMB and safety/efficacy is introduced.