Reimagining the Framework Supporting the Static Analysis of Transporter Drug Interaction Risk; Integrated Use of...

Area of Science:

• Pharmacology
• Drug Metabolism and Pharmacokinetics
• Biomarker Development

Background:

• Solute carrier (SLC) transporters are key sites for drug-drug interactions (DDIs).
• Current methods for assessing DDI risk, like static models using in vitro IC50 data, often lead to high false-positive rates and unnecessary clinical studies.
• Plasma and urine SLC biomarkers are being explored to better de-risk DDIs in early drug development.

Purpose of the Study:

• To develop and validate a predictive model for SLC-mediated DDIs using in vitro inhibition data and clinical biomarker information.
• To establish criteria for identifying compounds that pose a significant DDI risk, thereby optimizing the need for clinical DDI studies.
• To create a 'pan-SLC inhibition signature' for drug perpetrators to guide biomarker selection.

Main Methods:

• In-house in vitro SLC IC50 data were generated for clinically qualified perpetrator drugs.
• Estimated % inhibition for each SLC was empirically related to published clinical biomarker data (AUC ratio and % decrease in renal clearance).
• A 'calibration' exercise was performed to correlate in vitro inhibition with in vivo DDI outcomes.

Main Results:

• Compounds with high R values (>1.5) and Cmax,u/IC50 ratios (>0.5) were identified as likely to significantly modulate liver and renal biomarkers, indicating DDI risk.
• The predictive model suggests that only compounds exceeding these thresholds are likely to cause substantial liver (AUCR >1.25) and renal (ΔCLrenal >25%) DDIs.
• The % inhibition approach allows for the integration of liver and renal SLC data, enabling the generation of pan-SLC inhibition signatures.

Conclusions:

• The developed % inhibition approach provides a more accurate assessment of DDI risk compared to traditional static methods.
• This method can guide the selection of appropriate SLC biomarkers for Phase I studies, reducing the need for extensive drug probe-based studies.
• The findings support a more refined strategy for evaluating SLC-mediated DDIs, improving drug development efficiency.