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

Solute carrier (SLC) transporters present as the loci of important drug-drug interactions (DDIs). Therefore, sponsors generate in vitro half-maximal inhibitory concentration (IC₅₀ ) data and apply regulatory agency-guided "static" methods to assess DDI risk and the need for a formal clinical DDI study. Because such methods are conservative and high false-positive rates are likely (e.g., DDI study triggered when liver SLC R value ≥ 1.04 and renal SLC maximal unbound plasma (C_max,u )/IC₅₀ ratio ≥ 0.02), investigators have attempted to deploy plasma- and urine-based SLC biomarkers in phase I studies to de-risk DDI and obviate the need for drug probe-based studies. In this regard, it was possible to generate in-house in vitro SLC IC₅₀ data for various clinically (biomarker)-qualified perpetrator drugs, under standard assay conditions, and then estimate "% inhibition" for each SLC and relate it empirically to published clinical biomarker data (area under the plasma concentration vs. time curve (AUC) ratio (AUCR, AUC_inhibitor /AUC_reference ) and % decrease in renal clearance (ΔCL_renal )). After such a "calibration" exercise, it was determined that only compounds with high R values (> 1.5) and C_max,u /IC₅₀ ratios (> 0.5) are likely to significantly modulate liver (AUCR > 1.25) and renal (ΔCL_renal  > 25%) biomarkers and evoke DDI risk. The % inhibition approach supports integration of liver and renal SLC data and allows one to generate pan-SLC inhibition signatures for different test perpetrators (e.g., SLC % inhibition ranking). In turn, such signatures can guide the selection of the most appropriate individual (or combinations of) biomarkers for testing in phase I studies.