Table Of ContentH A
ANDBOOK OF NTICANCER
P P
HARMACOKINETICS AND HARMACODYNAMICS
C D D D
ANCER RUG ISCOVERY AND EVELOPMENT
B A. T , S E
EVERLY EICHER ERIES DITOR
Proteasome Inhibitors in Cancer Therapy, Targets for Cancer Chemotherapy:
edited by Julian Adams, 2004 Transcription Factors and Other
Nucleic Acid Therapeutics in Cancer, Nuclear Proteins, edited by Nicholas
edited by Alan M. Gewirtz, 2004 B. La Thangue and Lan R. Bandara,
Cancer Chemoprevention,Volume 1: 2002
Promising Cancer Chemopreventive Tumor Targeting in Cancer Therapy,
Agents,edited by Gary J. Kelloff, Ernest edited by Michel Pagé, 2002
T. Hawk, and Caroline C. Sigman, 2004 Hormone Therapy in Breast and Prostate
DNA Repair in Cancer Therapy, edited Cancer,edited by V. Craig Jordan and
byLawrence C. Panasci and Moulay Barrington J. A. Furr, 2002
A. Alaoui-Jamali, 2004 Tumor Models in Cancer Research,
Hematopoietic Growth Factors in Oncology: edited by Beverly A. Teicher, 2002
Basic Science and Clinical Therapeutics, Tumor Suppressor Genes in Human Cancer,
edited by George Morstyn, MaryAnn edited by David E. Fisher, 2001
Foote, and Graham J. Lieschke, 2004 Matrix Metalloproteinase Inhibitors in
Handbook of Anticancer Pharmacokinetics Cancer Therapy, edited by Neil J.
and Pharmacodynamics, edited by Clendeninn and Krzysztof Appelt, 2001
William D. Figg and Howard L. McLeod, Farnesyltransferase Inhibitors in Cancer,
2004 edited by Saïd M. Sebti and Andrew D.
Anticancer Drug Development Guide: Hamilton, 2001
Preclinical Screening, Clinical Trials, Platinum-Based Drugs in Cancer Therapy,
and Approval, Second Edition, edited edited by Lloyd R. Kelland and Nicholas
byBeverly A. Teicherand Paul A. P. Farrell, 2000
Andrews, 2004 Apoptosis and Cancer Chemotherapy,
Handbook of Cancer Vaccines, edited by edited by John A. Hickman and
Michael A. Morse, Timothy M. Clay, Caroline Dive, 1999
and Kim H. Lyerly, 2004 Signaling Networks and Cell Cycle Control:
Drug Delivery Systems in Cancer Therapy, The Molecular Basis of Cancer and Other
edited by Dennis M. Brown, 2003 Diseases, edited by J. Silvio Gutkind, 1999
Oncogene-Directed Therapies, edited Antifolate Drugs in Cancer Therapy,
byJanusz Rak, 2003 edited by Ann L. Jackman, 1999
Cell Cycle Inhibitors in Cancer Therapy: Antiangiogenic Agents in Cancer Therapy,
Current Strategies, edited by Antonio edited by Beverly A. Teicher, 1999
Giordano and Kenneth J. Soprano, Anticancer Drug Development Guide:
2003 Preclinical Screening, Clinical Tri-
Chemoradiation in Cancer Therapy, als, and Approval, edited by Beverly
edited by Hak Choy, 2003 A. Teicher, 1997
Fluoropyrimidines in Cancer Therapy, Cancer Therapeutics: Experimental and
edited by Youcef M. Rustum, 2003 Clinical Agents, edited by Beverly A.
Teicher,1997
H A
ANDBOOK OF NTICANCER
P
HARMACOKINETICS AND
P
HARMACODYNAMICS
Edited by
W D. F ,
ILLIAM IGG PharmD
Center for Cancer Research
National Cancer Institute, Bethesda, MD
and
H L. M L ,
OWARD C EOD PharmD
Washington University School of Medicine, St. Louis, MO
SPRINGER SCIENCE+BUSINESS
MEDIA, LLC
© 2004 Springer Science+Business Media New York
Originally published by Humana Press Inc. in 2004
Softcover reprint of the hardcover 1st edition 2004
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reflect the views of the publisher.
Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information
published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that
the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time
of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical
experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product
information provided by the manufacturer of each drug for any change in dosages or for additional warnings and
contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug.
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10 9 8 7 6 5 4 3 2 1
ISBN 978-1-4757-5345-5
Library of Congress Cataloging-in-Publication Data
Handbook of anticancer pharmacokinetics and pharmacodynamics / edited by
William D. Figg, Howard L. McLeod.
p. ; cm. -- (Cancer drug discovery and development)
Includes bibliographical references and index.
ISBN 978-1-4757-5345-5 ISBN 978-1-59259-734-5 (eBook)
DOI 10.1007/978-1-59259-734-5
1. Antineoplastic agents--Research--Handbooks, manuals, etc.
[DNLM: 1. Antineoplastic Agents--pharmacology. 2. Antineoplastic
Agents--pharmacokinetics. QV 269 H236 2004] I. Figg, William D. II.
McLeod, Howard L. III. Series.
RS431.A64H36 2004
616.99'4061--dc21 2003013963
--
P
REFACE
We embarked upon editing a text with the objective of having a single reference on
clinical pharmacology to serve as a guide to drug development with a focus on cancer
therapy. There are numerous textbooks that convey each of the components individually;
however, we envisioned a text that went beyond individual topics and developed the
Handbook of Anticancer Pharmacokinetics and Pharmacodynamics.
We have organized this handbook according to the following scheme (Figure 1), which
outlines a logical flow of events from identification of a cancer-specific target to phase
III clinical testing. This handbook includes two chapters that make it unique: “Identify-
ing Agents to Test in Phase III Trials” by Roberts, Lynch, and Chabner and “Clinical
Trials Designs for Approval of New Anticancer Agents: A Clinical Science” by Von
Hoff. Together these chapters give a roadmap for moving an agent toward NDA submis-
sion. This handbook should be of interest to both the clinical pharmacologist and the
pharmaceutical scientist.
Figure 1. Drug Development Plan
v
vi Preface
We would like to thank all of the authors for their thoughtful and thorough contribu-
tions. Our task of compiling this book was made easy by their high-quality efforts.
We would also like to thank our post-doctoral fellows and graduate students who have
stimulated us to continue to learn over the years. Furthermore, we appreciate the toler-
ance of our careers from our families and their continued support (Jennifer Figg and
William Figg, II and Donya, Katie, and Max McLeod). Lastly, we continue to be con-
scious of our patients who keep us focused on the goal of finding treatments and cures
for all types of cancer.
William D. Figg, PharmD
Howard L. McLeod, PharmD
C
ONTENTS
Preface............................................................................................................................v
Contributors...................................................................................................................xi
Ebook/PDA ..................................................................................................................xv
1 Molecular Targets
Udai Banerji, Ian Judson, and Paul Workman.................................................1
2 Preclinical Screening for New Anticancer Agents
Angelika M. Burger and Heinz-Herbert Fiebig..............................................29
3 Mouse Models in Cancer Drug Discovery and Development
Edward A. Sausville and Melinda Hollingshead.............................................45
4 Defining the Starting Dose:
2
Should It Be Based on mg/kg, mg/m , or Fixed?
Howard Gurney..................................................................................................57
5 Phase I Trials in Oncology: Design and Endpoints
James Cassidy....................................................................................................75
6 Analytical Methods: Development, Validation, and Clinical Applicability
Hans Ehrsson, Staffan Eksborg, and Jonas Bergh ........................................81
7 Validation and Control of Bioanalytical Methods
in Clinical Drug Development
H. Thomas Karnes.............................................................................................91
8 Clinical Pharmacology Overview
Andrew P. Beelen and Lionel D. Lewis..........................................................111
9 Pharmacokinetic Modeling
Sharyn D. Baker and Michelle A. Rudek.......................................................129
10 Pharmacodynamic Modeling
Kenneth S. Bauer and William P. Petros.......................................................139
11 Pharmacometric Knowledge-Based Oncology Drug Development
Paul J. Williams, James A. Uchizono, and Ene I. Ette.................................149
12 Protein Binding of Anticancer Drugs
Alex Sparreboom and Walter J. Loos.............................................................169
13 Metabolism (Non-CYP Enzymes)
Sally A. Coulthard and Alan V. Boddy ..........................................................189
14 Cytochrome P450 and Anticancer Drugs
Yuichi Ando......................................................................................................215
15 Polymorphisms in Genes of Drug Targets and Metabolism
and in DNA Repair
Jan Stoehlmacher, Syma Iqbal, and Heinz-Josef Lenz................................231
vii
viii Contents
16 Drug Interactions
Laurent P. Rivory.............................................................................................245
17 ABC Transporters: Involvement in Multidrug Resistance
and Drug Disposition
Susan E. Bates and Tito Fojo.........................................................................267
18 Intrathecal Chemotherapy
Jeff Stone and Susan M. Blaney ....................................................................289
19 Use of Microdialysis in Preclinical and Clinical Development
of Anticancer Agents
William C. Zamboni ........................................................................................307
20 Regional Therapy of Cancer Using Continuous Hyperthermic
Peritoneal Perfusion or Vascular Isolation and Perfusion Techniques
H. Richard Alexander, Maihgan A. Kavanagh, Steven K. Libutti,
and James F. Pingpank...............................................................................327
21 Isolated Lung Perfusion for the Treatment of Inoperable
Pulmonary Malignancies
David S. Schrump............................................................................................349
22 Pharmacokinetics of Isolated Lung Perfusion with Antitumor Agents
Suoping Zhai....................................................................................................363
23 Central Nervous System Malignancy and Clinical Pharmacology
Steve Y. Cho and Howard A. Fine..................................................................373
24 Pharmacokinetics of Anticancer Drugs in Children
Lisa C. Iacono, P. Kellie Turner, and Clinton F. Stewart...........................395
25 Clinical Pharmacokinetics in the Elderly
Patricia W. Slattum and Jürgen Venitz..........................................................421
26 The Combination of Angiogenesis Inhibitors and Radiotherapy
for the Treatment of Primary Tumors
Kevin Camphausen and Cynthia Ménard......................................................431
27 Gene Therapy for the Treatment of Cancer
H. Trent Spencer and Jacques Galipeau .......................................................439
28 Vaccines for the Treatment of Cancer
Philip M. Arlen, James Gulley, Lauretta Odogwu,
and John L. Marshall..................................................................................457
29 Pharmacokinetics of Antibodies and Immunotoxins in Mice and Humans
Victor Ghetie, E. Sally Ward, and Ellen S. Vitetta........................................475
30 Pharmacokinetics of Biologicals
Håkan Mellstedt, Jan-Erik Frödin, and Anders Österborg..........................499
31 Exposure–Response Relationship of Anticancer Agents: A Clinical
Pharmacology and Biopharmaceutics Regulatory Perspective
Atiqur Rahman ................................................................................................523
Contents ix
32 Identifying Agents to Test in Phase III Trials
Thomas G. Roberts Jr., Thomas J. Lynch Jr., and Bruce A. Chabner........539
33 Clinical Trial Designs for Approval of New Anticancer Agents:
A Clinical Science
Daniel D. Von Hoff .........................................................................................579
34 Pharmacogenetic Counseling
Jill M. Kolesar..................................................................................................593
Index...........................................................................................................................613
