Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

摘要: Microphysiological systems (MPS) provide relevant physiological environments in vitro for studies of pharmacokinetics, pharmacodynamics and biological mechanisms translational research. Designing multi-MPS platforms is essential to study multi-organ systems. Typical design approaches, including direct allometric scaling, scale each MPS individually are based on relative sizes not function. This study's aim was develop a new multi-functional scaling approach integrated platform specific applications. We developed an optimization using mechanistic modeling specification objective that considered multiple functions, e.g., drug absorption metabolism, simultaneously identify system parameters. informed the two hypothetical consisting gut liver (multi-MPS I) gut, kidney II) recapitulate vivo exposures vitro. allows establishment clinically exposure-response relationships, prerequisite efficacy toxicology assessment. Design parameters resulting from were compared designs scaling. Human plasma time-concentration profiles eight drugs used inform designs, additional five calculated test designed independent set. Multi-functional yielded exposure times good agreement with data, while approaches resulted short durations. appropriate platforms, cases studied provides better mimic than standard methods.