RT Journal Article
SR Electronic
T1 Breast Cancer Resistance Protein (ABCG2) in Clinical Pharmacokinetics and Drug Interactions: Practical Recommendations for Clinical Victim and Perpetrator Drug-Drug Interaction Study Design
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 490
OP 509
DO 10.1124/dmd.114.062174
VO 43
IS 4
A1 Caroline A. Lee
A1 Meeghan A. O’Connor
A1 Tasha K. Ritchie
A1 Aleksandra Galetin
A1 Jack A. Cook
A1 Isabelle Ragueneau-Majlessi
A1 Harma Ellens
A1 Bo Feng
A1 Mitchell E. Taub
A1 Mary F. Paine
A1 Joseph W. Polli
A1 Joseph A. Ware
A1 Maciej J. Zamek-Gliszczynski
YR 2015
UL http://dmd.aspetjournals.org/content/43/4/490.abstract
AB Breast cancer resistance protein (BCRP; ABCG2) 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 US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment 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. 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, immediate-release 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. In the case of rosuvastatin, subjects with the organic anion–transporting polypeptide 1B1 c.521T/T genotype are recommended, together with monitoring of rosuvastatin's cholesterol-lowering effect at baseline and DDI phase. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design.