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 confrontinga dilemma of ?so many papers and so few drugs?. A number of factors contribute to this. One significant factoris the development complexity pertaining to the physicochemical properties of liposomes, where a minutedifference may result in a radical change in in vivo performance and treatment efficacy. Another critical factor isa 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 aphysiologically-based pharmacokinetic (PBPK) modeling strategy to address these challenges. This strategydevelops a specialized PBPK platform for liposomal drugs that is expected to enable effective translations fromphysicochemical properties to in vivo performance, allowing early interactions between developers andregulators, 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 toguide experimental design; additionally, the experiment generates new knowledge to constrain PBPK modelsthat will benefit further experimentation. Liposomal doxorubicin (Doxil ) is chosen as a model drug. A genericmodel will step-wisely grow into a specialized PBPK platform along with the inclusion of more specificinformation 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 theliterature, seeking broad property-performance relationships for liposomes and then training these relationshipsin 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. Theseformulations will be prepared with modifications of the CQAs that are projected in Aim 1. This section will yieldmore specific knowledge to further confine and improve the generic PBPK model.
Aim 3 : Assess the PK andbiodistribution of the desired formulations. The formulation properties will match with in vivo performance toupdate PBPK model.
Aim 4 : Quantify the heterogeneous distribution of liposomes in solid tumors and explorethe determinants.
After Aim 4, the PBPK model will complete a cascade from ?formulation properties ? systemretention ? heterogeneous tumor disposition ? efficacy?.
Aim 5 : Model validation and translation. The modeltranslation to human will be performed by mechanism-based Monte Carlo Simulation. A ?virtual?bioequivalence study will be conducted.
Liposomes have shown strong promise as drug carriers delivering drugs to sites of action; however; greatchallenges remain in development of such drugs and their follow-on versions. This proposal is expected todevelop a specialized physiologically-based pharmacokinetic model (PBPK) platform to address thesechallenges. This specialized PBPK model is expected to enable effective translations from drugphysicochemical properties to their in vivo performance; allowing early interactions between developers andregulators; ultimately expediting liposomal drug development.
| He, Hua; Liu, Can; Wu, Yun et al. (2018) A Multiscale Physiologically-Based Pharmacokinetic Model for Doxorubicin to Explore its Mechanisms of Cytotoxicity and Cardiotoxicity in Human Physiological Contexts. Pharm Res 35:174 |
