UC San Francisco Electronic Theses and Dissertations
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UCSF UC San Francisco Electronic Theses and Dissertations Title Resolving the Conflict between BCS and BDDCS for the Advancement of the Drug Discovery, Development, and Regulatory Processes Permalink https://escholarship.org/uc/item/9wc7754r Author Larregieu, Caroline A. Publication Date 2014 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California ii I dedicate this to my parents, Joyce and Habeeb Zayne, who pushed me to strive to be the most independent, self-sufficient, and intellectual version of myself, and my husband, Vibs, without whom I simply could not do this. iii ACKNOWLEDGMENTS I feel extremely honored and privileged to be the 52nd doctoral student to have graduated under Dr. Leslie Z. Benet. For someone as accomplished as Les, it never ceases to amaze me how humble, approachable, and open-minded he is. I admire his ability to recognize raw talents and polish them to their full potential. Even though he can be extremely busy with his sea of commitments, he has always happily made himself available whenever I needed his guidance. I cannot express enough my deepest gratitude to Les for his nurturing mentorship, his unflailing support, and his unshakable confidence in me. I am grateful to have worked with numerous current and past students and fellows of the Benet lab, including Dr. Sarah B. Shugarts and Dr. Maribel Reyes for easing my transition into the lab; Dr. Hideaki Okochi for his tremendous breadth of knowledge, guidance, and help; Dr. Fabio Broccatelli for his brilliant collaborative work and stimulating discussions; Dr. Jason Baik for his insightful, intellectual, and philosophical balance; Alan R. Wolfe for voluntarily helping to keep lab operations smooth and in compliance; and Frances M. Peterson for being a fantastic support system and confidante. I would like to express my sincere appreciation to the entire Pharmaceutical Sciences and Pharmacogenomics (PSPG) family, including Dr. Kathleen M. Giacomini and Dr. Xin Chen for serving on my Thesis and Oral Qualifying Examination Committees; Dr. Deanna L. Kroetz and Dr. Laura Bull for serving on my Oral Qualifying Examination Committee; Dr. Kareen Riviere for being my senior mentor when I first joined the program; Dr. Lindsay M. Reynolds for being my favorite classmate and iv kindred spirit; and Debbie Acoba-Idlebi for always being available to counsel on graduate school and personal issues. A special mention must be made of my “sisters” of over 20 years – Sanola A. Daley, Rebekah L. Francis, Conniel A. Malek, Shushanna C. Mignott, and Dr. Cheryl S. Stewart – who never ceased to inspire and motivate me during this endeavor. It has meant the world to me to have the unconditional love and support of my family throughout this journey. I am indebted to my parents, Joyce and Habeeb Zayne, who have sacrificed beyond words can describe to provide me the best opportunities in life. I must also express my heartfelt love and appreciation for the rest of my family – notably my aunt, Jasmine Burke; my mother-in-law, Dr. Ranjna Jindal; my father-in-law, Dr. Vinod K. Jindal; my aunt-in-law, Asha Mansinghka; and my uncle-in-law, Dr. Surendra K. Mansinghka. Finally, I simply could not have arrived at this milestone without the unwavering support and relentless cheerleading of my anchor, my rock, my sanity, my best friend, my soul mate, and my husband – Vibhav “Vibs” Jindal – who I proudly share this achievement with. v ABSTRACT Drug permeability is accepted as a screening tool for determining intestinal absorption via the Biopharmaceutics Classification System (BCS) during the drug development and regulatory approval processes. Currently, predicting clinically significant drug interactions during drug development is a known challenge for the pharmaceutical industry and regulatory agencies. The Biopharmaceutics Drug Disposition Classification System (BDDCS), a modification of BCS utilizing drug metabolism instead of intestinal permeability, predicts drug disposition and potential drug-drug interactions in the intestine, the liver, and most recently the brain. While correlations between BCS and BDDCS have been observed with drug permeability, discrepancies in drug classification between the two systems using different permeability models, accepted as surrogate models for demonstrating human intestinal permeability by the FDA, have been noted. This project examines the role of drug permeability in drug absorption and drug metabolism and recommends the suitability of these models for predicting BDDCS and BCS classifications. This project evaluates methodologies that can lead to recommendations for facilitating the drug discovery, development, and regulatory approval processes. vi TABLE OF CONTENTS ACKNOWLEDGMENTS................................................................................................iv ABSTRACT.......................................................................................................................vi LIST OF TABLES............................................................................................................xi LIST OF FIGURES.........................................................................................................xii CHAPTER 1: UNDERSTANDING THE DIFFERENCES BETWEEN BCS AND BDDCS................................................................................................................................1 1.1 THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)...............................1 1.2 METHODS FOR ASSESSING BCS CLASSIFICATION................................................3 1.3 THE BIOPHARMACEUTICS DRUG DISPOSITION CLASSIFICATION SYSTEM (BDDCS)......................................................................................................................4 1.4 DISCREPANCIES BETWEEN CLASSIFYING DRUGS UNDER BCS AND BDDCS...8 1.5 GOALS AND HYPOTHESES.......................................................................................9 1.6 REFERENCES.............................................................................................................11 CHAPTER 2: INVESTIGATING AND IMPROVING IN SILICO AND IN VITRO PREDICTION MODELS THAT USE CACO-2 AS A SURROGATE FOR HUMAN INTESTINAL PERMEABILITY..................................................................................14 2.1 INTRODUCTION........................................................................................................14 2.2 IDENTIFYING COMPOUNDS FOR WHICH CACO-2 MAY POORLY PREDICT HUMAN INTESTINAL PERMEABILITY RATE MEASUREMENTS.........................17 2.2.1 Substrates of Highly Expressed Human Small Intestinal Transporters: Peptide, Amino Acid, and Nucleoside Transporters......................................................17 vii TABLE OF CONTENTS (continued) 2.2.2 Differences in the Paracellular Junctions between Caco-2 and the Human Intestine do not Explain the Inaccurate In Vitro–In Vivo Permeability Predictions by Caco-2 for Hydrophilic Compounds........................................25 2.3 THE NEED FOR LARGER, SINGLE-SOURCE CACO-2 PERMEABILITY RATE DATASETS.................................................................................................................28 2.4 IN SILICO WORK CONSIDERATIONS......................................................................32 2.5 IN VITRO SCREENING CONSIDERATIONS..............................................................41 2.6 REGULATORY CONSIDERATIONS..........................................................................43 2.7 CONCLUSIONS..........................................................................................................45 2.8 ACKNOWLEDGMENT...............................................................................................47 2.9 REFERENCES.............................................................................................................48 CHAPTER 3: DISTINGUISHING BETWEEN THE PERMEABILITY RELATIONSHIPS WITH ABSORPTION AND METABOLISM TO IMPROVE BCS AND BDDCS PREDICTIONS...............................................................................67 3.1 INTRODUCTION........................................................................................................67 3.2 METHODS..................................................................................................................70 3.2.1 Compilation of Permeability Rate Datasets.....................................................70 3.2.2 Correlations of BCS and BDDCS with Drug Permeability Rate Measures..........................................................................................................74 3.3 RESULTS....................................................................................................................81 viii TABLE OF CONTENTS (continued) 3.3.1 Comparison of BCS and BDDCS Classifications Using Human Intestinal Permeability Rate Measures............................................................................81 3.3.2 Comparison of BCS and BDDCS Classifications Using Caco-2 Permeability Rate Measures..................................................................................................85 3.3.3 Comparison of BCS and BDDCS Classifications Using PAMPA Permeability Rate Measures..................................................................................................91 3.4 DISCUSSION..............................................................................................................98 3.4.1 Use of BDDCS in the BCS FDA Guidance