High-Throughput SFC-MS/MS Method to Measure EPSA and Predict Human Permeability.

Area of Science:

• Drug Discovery and Development
• Pharmacokinetics and Drug Metabolism
• Computational Chemistry

Background:

• Drug permeability is crucial for oral absorption, but its early evaluation, especially for Lipinski's Rule of 5 violators, is difficult.
• Existing methods for permeability assessment can be time-consuming and lack sufficient sensitivity or selectivity.
• Accurate prediction of drug permeability is essential for efficient lead optimization and reducing late-stage failures.

Purpose of the Study:

• To establish a high-throughput method for measuring experimental polar surface area (HT-EPSA) as an in vitro surrogate for drug permeability.
• To evaluate the utility of HT-EPSA in predicting human in vitro and in vivo passive permeability.
• To demonstrate the application of HT-EPSA for rank-ordering permeability and improving decision-making in early drug discovery.

Main Methods:

• Development of a high-throughput assay to measure experimental polar surface area (HT-EPSA).
• Comparison of HT-EPSA with traditional methods regarding data acquisition time, sensitivity, selectivity, and data quality.
• Application of HT-EPSA for predicting Caco-2 cell and human intestinal permeability, including a proteolysis targeting chimera case study.

Main Results:

• HT-EPSA significantly reduces data acquisition time while enhancing sensitivity, selectivity, and data quality compared to previous methods.
• HT-EPSA demonstrated improved prediction of Caco-2 cell and human intestinal permeability over topological polar surface area and PAMPA.
• The method successfully rank-ordered permeability in a proteolysis targeting chimera case study, aiding compound selection.

Conclusions:

• The HT-EPSA method provides a robust and efficient in vitro surrogate for assessing drug permeability.
• HT-EPSA is valuable for early-stage compound rank-ordering and faster decision-making in drug discovery.
• This method shows promise for predicting in vitro and in vivo human intestinal permeability, optimizing drug development pipelines.