Is It Time to Use Modeling of Cellular Transporter Homeostasis to Inform Drug-Drug Interaction Studies: Theoretical...

Area of Science:

• Pharmacology
• Computational Biology
• Drug Development

Background:

• Mathematical modeling is crucial for pharmaceutical research and drug development efficiency.
• Previous work applied a multiscale model to nanoparticle disposition.
• This study focuses on intracellular processes and drug-drug interactions (DDIs).

Purpose of the Study:

• To demonstrate how disruption of transporter homeostasis can lead to DDIs.
• To identify key factors influencing DDI detection using a 4-scale model.
• To support model-informed drug development strategies.

Main Methods:

• Utilized a 4-scale model (cell membrane, intracellular organelles, spatial location, time).
• Integrated literature data on intracellular processing of membrane receptors and transporters.
• Developed computational components for transporter homeostasis, pharmacokinetics, and pharmacodynamics.

Main Results:

• Disruption of transporter internalization or recycling showed the highest incidence of DDIs.
• Minor DDIs were observed with perturbations in transporter synthesis and endosome trafficking.
• Spatial transporter distribution, co-incubation time, and extracellular concentrations determined DDI detection.

Conclusions:

• Mathematical modeling is valuable for generating hypotheses and designing experiments to identify potential DDIs.
• Simulations revealed that transporter internalization and recycling are critical pathways for DDI.
• The findings align with the FDA's model-informed drug development paradigm.