Development of an In Vitro System To Emulate an In Vivo Subcutaneous Environment: Small Molecule Drug Assessment

Abstract

A reliable in vitro system can support and guide the development of subcutaneous (SC) drug products. Although several in vitro systems have been developed, they have some limitations, which may hinder them from getting more engaged in SC drug product development. This study sought to develop a novel in vitro system, namely, Emulator of SubCutaneous Absorption and Release (ESCAR), to better emulate the in vivo SC environment and predict the fate of drugs in SC delivery. ESCAR was designed using computer-aided design (CAD) software and fabricated using the three-dimensional (3D) printing technique. ESCAR has a design of two acceptor chambers representing the blood uptake pathway and the lymphatic uptake pathway, respectively, although only the blood uptake pathway was investigated for small molecules in this study. Via conducting a DoE factor screening study using acetaminophen solution, the relationship of the output (drug release from the “SC” chamber to the “blood circulation” chamber) and the input parameters could be modeled using a variety of methods, including polynomial equations, machine learning methods, and Monte Carlo simulation-based methods. The results suggested that the hyaluronic acid (HA) concentration was a critical parameter, whereas the influence of the injection volume and injection position was not substantial. An in vitro–in vivo correlation (IVIVC) study was developed using griseofulvin suspension to explore the feasibility of applying ESCAR in formulation development and bioequivalence studies. The developed LEVEL A IVIVC model demonstrated that the in vivo PK profile could be correlated with the in vitro release profile. Therefore, using this model, for new formulations, only in vitro studies need to be conducted in ESCAR, and in vivo studies might be waived. In conclusion, ESCAR had important implications for research and development and quality control of SC drug products. Future work would be focused on further optimizing ESCAR and expanding its applications via assessing more types of molecules and formulations.

Development of Mechanistic In Vitro–In Vivo Extrapolation to Support Bioequivalence Assessment of Long-Acting Injectables

“…Physiologically-based pharmacokinetic (PBPK) modeling provides a unique opportunity to understand the in vivo mechanisms affecting an active pharmaceutical ingredient’s (API’s) local and systemic disposition and elimination; hence, it is a useful tool supporting the generic drug development process and approval [ 5 , 6 , 7 , 8 ]. Furthermore, physiologically-based biopharmaceutics modeling (PBBM) integrates in vitro dissolution and formulation characterization results into the model to predict a formulation’s in vivo behavior [ 5 ].…”

“…Furthermore, physiologically-based biopharmaceutics modeling (PBBM) integrates in vitro dissolution and formulation characterization results into the model to predict a formulation’s in vivo behavior [ 5 ]. The PBBM approach can be used to establish in vitro–in vivo correlations (IVIVCs), allowing prediction of the PKs of formulation variants based on their in vitro dissolution profiles [ 6 , 7 , 8 ]. The establishment of mechanistic IVIVCs is a valuable approach that may enable the understanding of the impact of individual formulation attributes on the in vivo release behavior of LAI formulations.…”

Development of UV–Vis Imaging Compatible Chromatographic Matrix with Application for Injectable Formulation Characterization

“…tissues has been proposed to resemble transport processes occurring in chromatography . In pharmaceutical research and drug development, there is an unmet need for characterization technologies with biopredictive capabilities for injectable formulations. − Various in vitro release testing approaches seeking to emulate selected features of the human body have been pursued attempting to improve our understanding of the complex processes occurring upon injection and until the drug substance reaches the circulation. − With few exceptions, chromatographic methods have exclusively been used for drug quantification upon sample removal from the in vitro release testing system. Imaging techniques are warranted for their ability to visualize physical changes and link these alterations to changes in chemical composition and are universally useful for elucidating processes and mechanisms.…”