Scientific Director Bristol Myers Squibb Company Princeton, New Jersey
Various ATP-binding cassette (ABC) transporters including P‐glycoprotein (P-gp) and breast cancer resistance protein (BCRP), highly expressed on the apical membrane of enterocytes, hepatocytes, kidney proximal tubule cells, and brain microvascular endothelial cells, are known to govern intestinal absorption, biliary excretion, urinary secretion, and brain penetration of their drug substrates. Any combination of the processes involving P-gp and BCRP can serve as the locus of systemic and tissue drug-drug interactions (DDIs) by potentially altering drug efficacy or toxicity. As a result, the FDA, EMA and PMDA have recommended that studies be performed to investigate whether an investigational drug is a substrate and/or inhibitor for P-gp and BCRP. However, translation of preclinical P-gp and BCRP in vitro and animal data to clinical findings remains challenging. This presentation aims to highlight recent advances in our understanding of the role of P-gp and BCRP in drug intestinal absorption and brain penetration. Novel and translational tools, such as quantitative proteomics methods, endogenous biomarkers, and intestinal P-gp and BCRP specific inhibitors, have been utilized to assess the impact of P-gp and BCRP on drug intestinal absorption and brain penetration in vivo. For example, recent investigations on the application of a proteomics‐informed approach helped predict steady‐state drug concentrations in the brain. Additionally, riboflavin was identified as an informative BCRP plasma biomarker in animal models. Ultimately riboflavin may shed light on the risk assessment of BCRP DDIs in early clinical trials if the utility of this biomarker is further validated in humans. Moreover, Encequidar may allow an in-depth appraisal of the role of the intestinal efflux P-gp and BCRP in drug disposition in animals and humans through local intestinal drug interactions. Development of translational in vitro assays and in vivo methods is critical to improve therapeutic outcomes and to evaluate the role of P-gp and BCRP in pharmacokinetic and pharmacological functions.
Learning Objectives:
There is an increasing interest in accurate prediction of the brain penetration of compounds. This presentation will summarize the in vivo, in vitro, and proteomics advancements toward understanding the contribution of P‐gp and/or BCRP in restricting the entry of compounds to the brain of either healthy or special populations.
Endogenous biomarkers are a useful tool for assessing DDIs involving transporters in early clinical trials. This talk will highlight recent advances in characterizing riboflavin as an informative BCRP plasma biomarker in animal models.
The intestinally, hepatically, and renally expressed P-gp and BCRP play a critical role in drug disposition. However, the individual contributions of intestinal and systemic (hepatic and renal) P-gp and BCRP roles to drug disposition are difficult to define. In this presentation, we will present the recent advances in evaluating Encequidar as an intestinal P-gp and BCRP specific inhibitor to investigate their role in drug disposition.