The development of generic liposomal drug products face challenges because of a lack of in vitro release methods that correlate with in vivo performance. This study aims to evaluate different in vitro release assays of Ambisome-like formulations with respect to their capacity in detecting formulation differences that predict in vivo release of liposomal drug products. The overall goal is to devise robust and predictive amphotericin B (AmB) in vitro release assay or assays and validate them. To accomplish this, we will generate AmB liposome formulations with explicit variations in: liposome size distribution, lipid source, and method of production. A battery of in vitro assays, and maximum tolerated dose (MTD) and pharmacokinetics (PK) will be conducted. Assays that correlate with in vivo results will be identified. The combination of formulations and release assays will enable us to test the hypotheses that 1) in vitro release assays can be devised that enable the identification of generic AmB liposome formulations that have statistically indistinguishable pharmaceutical characteristics and AmB transfer/release properties from the innovator product Ambisome so that the maximum tolerated dose will be within allowable limits.
Aim 1. Prepare and characterize a series of liposome formulations that span the range of compositions, source of materials and preparation methods that can be encompassed by the product description of Ambisome.
Aim 2. Devise and validate multiple drug release assays using the liposomes created in Aim 1 that define release. The innovator product Ambisome will serve as the gold standard for setting the operating conditions that lead to reproducible release of drug as a function of time until 60% of the AmB content of the liposome is released or transferred from the liposome.
Aim 3. Conduct MTD and PK studies in rodents with selected drug formulations.
Aim 4. Identify those drug release assays that best correlate with in vivo studies. Results from this study will provide mechanistic information on what liposomal AmB formulation variables with the greatest impact on bioequivalence, advance the regulatory review process and ultimately improve public access to quality generic AmB liposomal drug products.
The development of generic liposomal drug products of amphotericin b face challenges because of a lack of compendial or bio-relevant in vitro release methods. These challenges contribute to the limited access to essential medicines in many countries. This study aims to evaluate different in vitro release assays in terms of their capacity in detecting formulation differences and predicting in vivo release of liposomal drug products.
