Evaluation of Drug Candidates for Preclinical Development: Pharmacokinetics, Metabolism, Pharmaceutics, and Toxicology (Wiley Series in Drug Discovery and Development)

304 Pages·2010·1.45 MB·English

by  Chao Han

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
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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
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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