ABSTRACT
Mechanistic-understanding-based selection of excipients may improve formulation development strategies for generic drug products and potentially accelerate their approval. Our study aimed at investigating the effects of molecular excipients present in orally administered FDA-approved drug products on the intestinal efflux transporter, BCRP (ABCG2), which plays a critical role in drug absorption with potential implications on drug safety and efficacy. We determined the interactions of 136 oral molecular excipients with BCRP in isolated membrane vesicles and identified 26 excipients as BCRP inhibitors with IC50 values less than 5 µM using 3H-cholecystokinin octapeptide (3H-CCK8). These BCRP inhibitors belonged to three functional categories of excipients: dyes, surfactants, and flavoring agents. Compared with noninhibitors, BCRP inhibitors had significantly higher molecular weights and SLogP values. The inhibitory effects of excipients identified in membrane vesicles were also evaluated in BCRP-overexpressing HEK293 cells at similar concentrations. Only 1 of the 26 inhibitors of BCRP identified in vesicles inhibited BCRP-mediated 3H-oxypurinol uptake by more than 50%, consistent with the notion that BCRP inhibition depends on transmembrane or intracellular availability of the inhibitors. Collectively, the results of this study provide new information on excipient selection during the development of drug products with active pharmaceutical ingredients that are BCRP substrates.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Coloring Agents/metabolism , Excipients/metabolism , Flavoring Agents/metabolism , Neoplasm Proteins/metabolism , Surface-Active Agents/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Administration, Oral , Coloring Agents/chemistry , Coloring Agents/pharmacology , Drug Compounding/methods , Drug Evaluation, Preclinical/methods , Excipients/chemistry , Excipients/pharmacology , Female , Flavoring Agents/chemistry , Flavoring Agents/pharmacology , HEK293 Cells , Humans , Inhibitory Concentration 50 , Intestinal Absorption/drug effects , Molecular Weight , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Signal Transduction/genetics , Surface-Active Agents/chemistry , Surface-Active Agents/pharmacology , TransfectionABSTRACT
This publication summarizes the proceedings of day 2 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Patient-centric drug product development from a drug product quality perspective necessitates the establishment of clinically relevant drug product specifications via an in vitro-in vivo link. Modeling and simulation offer a path to establish this link; in this regard, physiologically based modeling has been implemented successfully to support regulatory decision-making and drug product labeling. In this manuscript, case studies of physiologically based biopharmaceutics modeling (PBBM) applied to drug product quality are presented and summarized. These case studies exemplify a possible path to achieve an in vitro-in vivo link and encompass (a) development of biopredictive dissolution methods to support biowaivers, (b) model-informed formulation selection, (c) predicting clinical formulation performance, and (d) defining a safe space for regulatory flexibility via virtual bioequivalence (BE). Workflows for the development and verification of absorption models/PBBM and for the establishment of a safe space using dissolution as an input are described with examples. Breakout session discussions on topics, such as current challenges and some best practices in model development and verification, are included as part of the Supplementary material.
Subject(s)
Biological Products/pharmacokinetics , Biopharmaceutics/methods , Drug Development/methods , Models, Biological , Absorption, Physiological , Biopharmaceutics/standards , Clinical Trials as Topic/methods , Clinical Trials as Topic/standards , Congresses as Topic , Drug Development/standards , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/standards , Drug Labeling/standards , Drug Liberation , Humans , Solubility , Therapeutic EquivalencyABSTRACT
BACKGROUND: Acupressure on the "extra 1" point decreases bispectral index (BIS) values and stress. METHODS: We investigated the BIS, melatonin, beta-endorphin, and verbal stress score values before, after 10 min of acupressure application on the extra 1 point, on a sham point, after no acupressure, and 1 h after completion of each intervention in 12 volunteers. RESULTS: The BIS and verbal stress score values were decreased after acupressure on the extra 1 point (P = 0.0001 and P = 0.008, respectively), but melatonin and beta-endorphin did not change. CONCLUSION: Acupressure on the extra 1 point has no effect on melatonin and beta-endorphin levels.