With recent increasing interest in novel modeling and simulation approaches for facilitating product development and bioequivalence study, a predictive, mechanistic model is a necessity for PLGA formulations. We developed a fully mechanistic PBPK model for PLGA implants which encapsulates the following underlying processes leading to drug release and its subsequent disposition: interstitial fluid influx into porous structure of implant; initial non-catalytic hydrolysis of PLGA while concentration of acid end groups is low; autocatalytic hydrolysis phase when catalyst concentration is pronounced; dissolution of small oligomers into aqueous medium characterised by mass loss of polymer and growing pore network; liberation of trapped solid drug from formulation; dissolution of solid drug into wetted pore network and its diffusion out of the implant through interconnected pores and; drug permeation through local tissues and distributions into systemic compartment. Model performance was verified using in vitro/in vivo data for subcutaneous Buserelin and intravitreal Brimonidine implants.
Learning Objectives:
Understand the ability of modelling and simulation to predict the behaviour of PLGA implants which can be used as a powerful tool for product development and bioequivalence of such formulations
Identify the effect of critical quality attributes of PLGA implants on drug release and sytemic exposure using a mechanitic PBPK model
Understand the ability of a mechanitic PBPK model to bridge in vitro release data and in vivo animal data to predict human in vivo behaviour of PLGA implants
