This presentation by Sean Hirschler focused on long-acting injectables (LAIs) in the context of biopharmaceutics and drug product design. Sean began by highlighting GSK's commitment to the three Rs: replacement, reduction, and refinement of animal studies, alongside a general animal welfare statement.
Sean explained that LAI drug products were designed to have unique pharmacokinetic (PK) characteristics, typically characterised by a long-term half-life due to slow release from the injection site and a slower rate of drug absorption compared to the rate of elimination. This phenomenon was referred to as flip-flop kinetics. The terminal phase of the PK profile of LAIs reflected the rate of systemic uptake from the injection site rather than elimination. LAIs could be administered intramuscularly (IM) or subcutaneously (SC), with main therapeutic areas including schizophrenia, contraception, and infectious diseases like HIV.
The advantages of LAIs included extended duration of action, reduced dosing frequency, and improved patient compliance and adherence. Sean illustrated the differences in PK profiles between oral assets and LAI formulations, noting that LAIs had blunted C Max, extended T Max, and longer half-lives. Formulation design was crucial in improving PK performance and impacting dose frequency.
Sean emphasised the importance of a cross-functional approach in LAI drug product design and development, involving collaboration and communication across teams for both drug substance and drug product. He acknowledged the challenges in LAI product development, such as animal-to-human translation and changes in excipient levels, drug form, and particle size. Biopharmaceutics played a significant role in influencing product performance throughout the development phase.
Sean discussed the paradigm shift from oral to long-acting injectables, starting with cabotegravir CABENUVA, which demonstrated the potential of leveraging inherent molecule properties to develop more LAIs. He outlined various work streams within GSK, including in vitro biopredictive dissolution, in vivo bioimaging, and in silico modelling, aimed at understanding product performance and mechanistic understanding of LAIs.
The ultimate goal was to develop a fully predictive mechanistic model to accelerate formulation selection, reduce animal use, and predict human performance of new formulations. Sean concluded by expressing the aspiration to integrate material properties into an LAI manufacturing process mechanistic model to predict in vivo PK.
