Clinical Assessment of Drug Transporter Inhibition Using Biomarkers: Review of the Literature (2015–2024)

Abstract As part of a narrative review of various publications describing the clinical use of urine‐ and plasma‐based drug transporter biomarkers, it was determined that the utilization of coproporphyrin I, a hepatic organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 biomarker, has been reported for 28 different drug–drug interaction (DDI) perpetrator drugs. Similarly, biomarkers for liver organic cation transporter 1 (isobutyryl‐ l ‐carnitine, N = 7 inhibitors), renal organic cation transporter 2 and multidrug and toxin extrusion proteins (N 1 ‐methylnicotinamide, N = 13 inhibitors), renal organic anion transporter (OAT) 1 and 3 (pyridoxic acid, N = 7 inhibitors), and breast cancer resistance protein (riboflavin, N = 3 inhibitors) have also been described. Increased use of biomarkers has also been accompanied by modeling efforts to enable DDI predictions and development of multiplexed methods to facilitate their bioanalysis. Overall, there is consensus that exploratory biomarkers such as coproporphyrin I can be integrated into decision trees encompassing in vitro transporter inhibition data, DDI risk assessments, and follow‐up Phase 1 studies. Therefore, sponsors can leverage biomarkers to evaluate dose‐dependent inhibition of selected transporters, use them jointly with drug probes to deconvolute DDI mechanisms, and integrate in vitro data packages to establish calibrated (biomarker informed) DDI risk assessment cutoffs. Although transporter biomarker science has progressed, reflected by its inclusion in the recently issued International Council for Harmonisation DDI guidance document (M12), some biomarkers still require further validation. There is also a need for biomarkers that can differentiate specific transporters (e.g., OATP1B3 vs OATP1B1 and OAT1 vs OAT3).