Physiologically Based Pharmacokinetic Model for Drugs Encapsulated into Liposomes

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ABSTRACT Despite the great promise held for liposomes in drug delivery and the number of liposomal drugs approved, challenges remain in development of such drugs and their follow-on versions. Currently, this field is confronting a dilemma of “so many papers and so few drugs”. A number of factors contribute to this. One significant factor is the development complexity pertaining to the physicochemical properties of liposomes, where a minute difference may result in a radical change in in vivo performance and treatment efficacy. Another critical factor is a lack of effective strategies to leverage the mounting research and knowledge in drug development. Development complexity also poses challenges to regulatory decision-making. Here we propose a physiologically-based pharmacokinetic (PBPK) modeling strategy to address these challenges. This strategy develops a specialized PBPK platform for liposomal drugs that is expected to enable effective translations from physicochemical properties to in vivo performance, allowing early interactions between developers and regulators, ultimately expediting drug development. A key feature of this strategy is to integrate “model” and “experiment” in a dynamic and sequential manner. On one side, PBPK models provide a prior simulation to guide experimental design; additionally, the experiment generates new knowledge to constrain PBPK models that will benefit further experimentation. Liposomal doxorubicin (Doxil®) is chosen as a model drug. A generic model will step-wisely grow into a specialized PBPK platform along with the inclusion of more specific information about liposomal doxorubicin either by rigorous literature research or additional experiments. Five Specific Aims are: Aim 1: Build a library-based generic PBPK model for liposomal drugs to train literature- derived property-performance relationships. The objective is to leverage the vast amount of knowledge in the literature, seeking broad property-performance relationships for liposomes and then training these relationships in a library-based generic PBPK model to explore potential Critical Quality Attributes (CQAs). Aim 2: Preparation, characterization, and in vitro studies of a series of PEGylated liposomal doxorubicin. These formulations will be prepared with modifications of the CQAs that are projected in Aim 1. This section will yield more specific knowledge to further confine and improve the generic PBPK model. Aim 3: Assess the PK and biodistribution of the desired formulations. The formulation properties will match with in vivo performance to update PBPK model. Aim 4: Quantify the heterogeneous distribution of liposomes in solid tumors and explore the determinants. After Aim 4, the PBPK model will complete a cascade from “formulation properties → system retention → heterogeneous tumor disposition → efficacy”. Aim 5: Model validation and translation. The model translation to human will be performed by mechanism-based Monte Carlo Simulation. A “virtual” bioequivalence study will be conducted.