Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using...

Area of Science:

• Biomedical Engineering
• Translational Research
• Pharmacology

Background:

• Microphysiological systems (MPS) offer in vitro physiological environments for pharmacokinetic, pharmacodynamic, and mechanistic studies.
• Current multi-MPS platform design relies on individual scaling (direct, allometric) based on size, not function, limiting translational research.
• Integrated multi-organ systems require advanced design approaches for accurate in vitro recapitulation of in vivo conditions.

Purpose of the Study:

• To develop and validate a novel multi-functional scaling approach for integrated multi-MPS platform design.
• To optimize multi-MPS platforms for specific applications by considering multiple organ functions simultaneously.
• To improve the recapitulation of in vivo drug exposures in vitro for enhanced efficacy and toxicology assessment.

Main Methods:

• Developed an optimization approach using mechanistic modeling and a multi-objective function.
• Incorporated simultaneous consideration of multiple MPS functions (e.g., drug absorption, metabolism).
• Informed designs using human plasma time-concentration profiles of eight drugs and validated with five additional drugs.

Main Results:

• Multi-functional scaling yielded in vitro exposure times closely matching in vivo data.
• Standard scaling methods (direct, allometric) resulted in significantly shorter in vitro exposure durations.
• The designed multi-MPS platforms (gut-liver, gut-liver-kidney) effectively mimicked in vivo drug exposures.

Conclusions:

• Multi-functional scaling provides a superior method for scaling multi-MPS platforms from in vivo to in vitro.
• This approach enables the establishment of clinically relevant drug exposure-response relationships.
• The developed method enhances the predictive power of MPS for drug development and safety assessment.