title: Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS).
abstract: Microphysiological systems (MPS) provide relevant physiological environments in vitro for studies of pharmacokinetics, pharmacodynamics and biological mechanisms for translational research. Designing multi-MPS platforms is essential to study multi-organ systems. Typical design approaches, including direct and allometric scaling, scale each MPS individually and are based on relative sizes not function. This study's aim was to develop a new multi-functional scaling approach for integrated multi-MPS platform design for specific applications. We developed an optimization approach using mechanistic modeling and specification of an objective that considered multiple MPS functions, e.g., drug absorption and metabolism, simultaneously to identify system design parameters. This approach informed the design of two hypothetical multi-MPS platforms consisting of gut and liver (multi-MPS platform I) and gut, liver and kidney (multi-MPS platform II) to recapitulate in vivo drug exposures in vitro. This allows establishment of clinically relevant drug exposure-response relationships, a prerequisite for efficacy and toxicology assessment. Design parameters resulting from multi-functional scaling were compared to designs based on direct and allometric scaling. Human plasma time-concentration profiles of eight drugs were used to inform the designs, and profiles of an additional five drugs were calculated to test the designed platforms on an independent set. Multi-functional scaling yielded exposure times in good agreement with in vivo data, while direct and allometric scaling approaches resulted in short exposure durations. Multi-functional scaling allows appropriate scaling from in vivo to in vitro of multi-MPS platforms, and in the cases studied provides designs that better mimic in vivo exposures than standard MPS scaling methods.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, USA. mcirit@mit.edu.
authors.forename: Christian
authors.identifier: 0000-0001-7618-0421
authors.initials: C
authors.lastname: Maass
authors.affiliation: Stokes Consulting, Redwood City, USA.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Stokes
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, USA. mcirit@mit.edu.
authors.forename: Linda G
authors.initials: LG
authors.lastname: Griffith
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, USA. mcirit@mit.edu.
authors.forename: Murat
authors.initials: M
authors.lastname: Cirit
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D010599:Pharmacokinetics; D057170:Translational Research, Biomedical