Nonclinical Testing Evaluation of Liposomes as Drug Delivery Systems.

ABSTRACT

Various marketed drugs, as well as many in-development, have utilized liposomes, vesicles composed of one or more phospholipid bilayers, as a drug delivery system, often with the statement that they are "non-toxic" materials. This paper examined safety testing considerations and reviewed nonclinical packages used to support the safe clinical use and marketing of drugs using a liposomal drug delivery system, including liposome-only study findings. It was found that most experience has come from use of an established drug (especially in the oncology field) in a liposome formulation with known excipients. From this knowledge, it is proposed that the minimal package of studies (using an oncology indication as an example) needed to support clinical entry should include in vivo pharmacology in selected mouse xenograft models, pharmacokinetic characterization showing enhanced kinetics or disposition and including tumor exposure evaluation along with repeat-dose toxicity testing in one species. It was also found that the liposomes used in drug delivery systems are not truly "non-toxic" materials. However, the majority of findings in toxicity testing relate to macrophage processing of large amounts of lipid material, with no human known safety consequence. Of note, however, are cases of hypersensitivity for some PEGylated liposome forms which translate to the clinic.