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EVALUATION of DRUG CANDIDATES for PRECLINICAL DEVELOPMENT Pharmacokinetics, Metabolism, Pharmaceutics, and Toxicology

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EVALUATION of DRUG CANDIDATES for PRECLINICAL DEVELOPMENT Pharmacokinetics, Metabolism, Pharmaceutics, and Toxicology EVALUATION OF DRUG CANDIDATES FOR PRECLINICAL DEVELOPMENT Pharmacokinetics, Metabolism, Pharmaceutics, and Toxicology Edited by CHAO HAN Centocor Research and Development Inc. CHARLES B. DAVIS GlaxoSmithKline BINGHE WANG Georgia State University A JOHN WILEY & SONS, INC., PUBLICATION EVALUATION OF DRUG CANDIDATES FOR PRECLINICAL DEVELOPMENT drug discovery-cp.qxd 11/14/2009 7:40 AM Page 1 Wiley Series in Drug Discovery and Development Binghe Wang, Series Editor Drug Delivery: Principles and Applications Edited by Binghe Wang, Teruna Siahaan, and Richard A. Soltero Computer Applications in Pharmaceutical Research and Development Edited by Sean Ekins Glycogen Synthase Kinase-3 (GSK-3) and Its Inhibitors: Drug Discovery and Development Edited by Ana Martinez, Ana Castro, and Miguel Medina Drug Transporters: Molecular Characterization and Role in Drug Disposition Edited by Guofeng You and Marilyn E. Morris Aminoglycoside Antibiotics: From Chemical Biology to Drug Discovery Edited by Dev P. Arya Drug-Drug Interactions in Pharmaceutical Development Edited by Albert P. Li Dopamine Transporters: Chemistry, Biology, and Pharmacology Edited by Mark L. Trudell and Sari Izenwasser Drug Design of Zinc-Enzyme Inhibitors: Functional, Structural, and Disease Applications Edited by Claudiu T. Supuran and Jean-Yves Winum ABC Transporters and Multidrug Resistance Edited by Ahcene Boumendjel, Jean Boutonnat, and Jacques Robert Kinase Inhibitor Drugs Edited by Rongshi Li and Jeffrey A. Stafford Evaluation of Drug Candidates for Preclinical Development: Pharmacokinetics, Metabolism, Pharmaceutics, and Toxicology Edited by Chao Han, Charles B. Davis, and Binghe Wang EVALUATION OF DRUG CANDIDATES FOR PRECLINICAL DEVELOPMENT Pharmacokinetics, Metabolism, Pharmaceutics, and Toxicology Edited by CHAO HAN Centocor Research and Development Inc. CHARLES B. DAVIS GlaxoSmithKline BINGHE WANG Georgia State University A JOHN WILEY & SONS, INC., PUBLICATION Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved. Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifi cally disclaim any implied warranties of merchantability or fi tness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profi t or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data: Evaluation of drug candidates for preclinical development : pharmacokinetics, metabolism, pharmaceutics, and toxicology / [edited by] Chao Han, Charles B. Davis, Binghe Wang. p. ; cm. Includes index. ISBN 978-0-470-04491-9 (cloth) 1. Drug development. 2. Pharmacokinetics. 3. Drugs–Metabolism. I. Han, Chao. II. Davis, Charles B. (Charles Baldwin) III. Wang, Binghe, PhD. [DNLM: 1. Drug Evaluation, Preclinical. 2. Drug Discovery. 3. Drug Industry– standards. 4. Pharmaceutical Preparations–metabolism. 5. Pharmacology–methods. QV 771 E917 2010] RM301.25.E93 2010 615′.19–dc22 2009035876 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1 CONTENTS PREFACE vii CONTRIBUTORS ix 1. INTRODUCTION 1 Charles B. Davis 2. PHARMACOKINETICS IN PRECLINICAL DRUG DEVELOPMENT: AN OVERVIEW 11 Dion Brocks 3. THE ROLE OF MEMBRANE TRANSPORTERS IN DRUG DISPOSITION 39 Fanfan Zhou, Peng Duan, and Guofeng You 4. CYTOCHROME P450: STRUCTURE, FUNCTION, AND APPLICATION IN DRUG DISCOVERY AND DEVELOPMENT 55 Ramesh B. Bambal and Stephen E. Clarke 5. THE ROLE OF DRUG METABOLISM AND METABOLITE IDENTIFICATION IN DRUG DISCOVERY 109 Xiangming Guan 6. PROTEIN BINDING IN DRUG DISCOVERY AND DEVELOPMENT 135 Vikram Ramanathan and Nimish Vachharajani v vi CONTENTS 7. PREDICTION OF THE PHARMACOKINETICS IN HUMANS 169 Chao Han and Ramesh Bambal 8. PHARMACEUTICS DEVELOPABILITY ASSESSMENT 187 Lian Huang, Jinquan Dong, and Shyam Karki 9. SAFETY ASSESSMENT IN DRUG DISCOVERY 221 Vito G. Sasseville, William R. Foster, and Bruce D. Car 10. ASSESSMENT OF STRATEGIES UTILIZED TO MINIMIZE THE POTENTIAL FOR INDUCTION OF ACQUIRED LONG QT SYNDROME AND TORSADE DE POINTES 253 Khuram W. Chaudhary and Barry S. Brown INDEX 281 PREFACE In the past two decades, the pharmaceutical industry has experienced tremendous transformation. There have been signifi cant scientifi c advances with the potential to revolutionize the treatment of human disease. Advanced technologies and automation have increased effi - ciency in the laboratory. Productivity of the industry as a whole, however, has not met the high expectations of society. As mature products lose patent protection pharmaceutical companies have strug- gled to fi ll gaps in their pipelines. Reorganization in the industry is commonplace; a wave of mega - mergers is under way as this book goes to press. Despite these challenges, small biotechnology companies and academic researchers continue to enter the fray, and competition in the industry remains fi erce. Outsourcing of diverse discovery and develop- ment activities is increasingly common as the industry attempts to minimize infrastructure and maximize fi nancial fl exibility. These adap- tations refl ect the high attrition rates experienced during development, increasing costs, and the increased expectations of society that new medicines will be safe, effective, and affordable. It is in this complex and dynamic context that we edit this book on the preclinical evalua- tion of drug candidates. We believe that selecting the “ right ” drug candidate for develop- ment is key to success. To lower attrition rates during early clinical development, pharmaceutical as well as pharmacological properties of the molecule should be optimized. This undertaking requires good science, perseverance, and often luck. There is precedence that the evaluation and optimization of pharmacokinetic properties early in drug discovery has a positive impact on the effort to lower attrition rates. We believe this example can be extended further and that a comprehensive evaluation of candidate developability at an early stage is an essential step. This book presents three major scientifi c areas: pharmacokinetics and drug metabolism, pharmaceutical development, and safety assess- vii viii PREFACE ment. The various properties of a new chemical entity are typically evaluated by groups of scientists with diverse backgrounds and exqui- site specialization, often working in isolation. Given the great potential for experimental fi ndings in one discipline to profoundly infl uence outcomes in another, integration is essential. Our goal is not to empha- size the leading edge of science and technology but rather to stress the integration of activities and information essential for the advancement of new medicines during drug development. We expect this book will enhance the formulation of appropriate strategies for compound pro- gression and improve decision- making. We hope this book will be valuable to readers from academia, industry, and service organizations, and thank the contributors for their dedication and patience. C hao H an Centocor Research and Development Inc. C harles B. D avis GlaxoSmithKline Pharmaceuticals B inghe W ang Georgia State University CONTRIBUTORS R amesh B. B ambal , Absorption Systems, Exton, Pennsylvania D ion R. B rocks , University of Alberta, Edmonton, AB, Canada B arry S. B rown , Department of Safety Pharmacology, GlaxoSmithKline B ruce D. C ar , Bristol - Myers Squibb Research and Development K huram W. C haudhary , Department of Safety Pharmacology, GlaxoSmithKline S tephen E. C larke , Preclinical Development, Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Pharmaceuticals, Ware, United Kingdom C harles B. D avis , Cancer Research, GlaxoSmithKline Pharmaceu- ticals J inquan D ong , Johnson & Johnson PRD P eng D uan , Department of Pharmaceutics, Rutgers University W illiam
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