Caroline A Lee, Meeghan A O'Connor, Tasha K Ritchie, Aleksandra Galetin, Jack A Cook, Isabelle Ragueneau-Majlessi, Harma Ellens, Bo Feng, Mitchell E Taub, Mary F Paine, Joseph W Polli, Joseph A Ware, Maciej J Zamek-Gliszczynski

BCRP limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Based on clinical evidence of BCRP-mediated drug-drug interactions (DDIs) and the c.421C>A functional polymorphism affecting drug efficacy and safety, both the FDA and EMA recommend preclinical evaluation, and when appropriate, clinical evaluation of BCRP-mediated DDIs. Although many BCRP substrates and inhibitors have been identified in vitro, clinical translation has been confounded by overlap with other transporters and metabolic enzymes. Thus, mechanistic attribution of clinical DDIs to BCRP has been equivocal. Regulatory recommendations for BCRP-mediated clinical DDI studies are challenging, as consensus is lacking on the choice of the most robust and specific human BCRP substrates and inhibitors and optimal study design. This review proposes a path forward based on a comprehensive analysis of available data. Oral sulfasalazine (1000 mg, IR tablet) is the best available clinical substrate for intestinal BCRP, oral rosuvastatin (20 mg) for both intestinal and hepatic BCRP, and intravenous rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000 mg) and lapatinib (250 mg) are the best available clinical BCRP inhibitors. To interrogate the worst-case clinical BCRP DDI scenario, study subjects harboring the BCRP c.421C/C reference genotype are recommended. In addition, if sulfasalazine is selected as the substrate, subjects having the rapid acetylator phenotype are recommended, whereas if rosuvastatin is selected, subjects harboring the OATP1B1 c.521T/T reference genotype are recommended. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design.