Table Of ContentHandbook of
Pharmacokinetic/
Pharmacodynamic
Correlation
handbooks of
O h &harmacology
■ W and
t
a ooxxicology
A CRC Press Series
Mannfred A. Hollinger, Series Editor
University of California, Davis
Published Titles
Handbook of Pharmacokinetic and Pharmacodynamic Correlations
with Computer Applications
Hartmut Derendorf
Handbook of Methods in Gastrointestinal Pharmacology
Timothy S. Gaginella
Handbook of Targeted Delivery of Imaging Agents
Vladimir P. Torchilin
Handbook of Pharmacology of Aging, Second Edition
Jay Roberts, David L. Snyder, and Eitan Friedman
Handbook of Plant and Fungal Toxicants
J. P. Felix D’Mello
Forthcoming Titles
Handbook of Theoretical Models in Biomedical Research
David B. Jack
Handbook of Mammalian Models in Biomedical Research
David B. Jack
Handbook of Opportunistic Infections
Vassil St. Georgiev
Handbook of Immunotoxicological Methods
Leonard Ritter
Handbook of
Pharmacokinetic/
Pharmacodynamic
Correlation
Edited by
Hartmut Derendorf, Ph. D.
Gunther Hochhaus, Ph.D.
University of Florida
Gainesville, Florida
Boca Raton London New York
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Introduction
It is a truism that the rate-limiting factor in the advance of most sciences is the ability to measure
those things that are relevant to the particular scientific discipline. Progress in pharmacokinetics, the
science devoted to the study of drug absorption, distribution, metabolism, and excretion processes,
was determined largely by the availability of sensitive and specific analytical methods to describe the
time course of drug and drug metabolite concentrations in biologic fluids and tissues. Most of the
mathematical techniques or models to characterize pharmacokinetic processes could be and were
taken from chemical kinetics, physiology, and enzymology, Much has been learned by applying these
analytical and mathematical techniques in properly designed studies. It was found, for example, that
some drugs are incompletely absorbed or partly metabolized during absorption; some distribution,
binding, transport, and biotransformation processes are readily saturable (nonlinear) in the therapeutic
concentration range of drugs; many drug biotransformation processes can be highly variable due to
genetic, environmental, and pathophysiologic factors. These findings and the relative ease of
measuring drug and drug metabolite concentrations have stimulated extensive research in pharmaco-
kinetics. Many scientists engaged in drug metabolism and pharmacokinetic studies believe that
interindividual differences in the clinical response to drugs are almost always due to corresponding
differences in pharmacokinetics.
It is only relatively recently that an increasing number of pharmaceutical scientists and clinical
pharmacologists have begun to focus on pharmacodynamics, the science that relates the time course
of drug concentrations to the time course of pharmacologic effects in humans and animals. This was
absolutely essential for the development of rational pharmacotherapeutics because pharmacodynamics
determines the target drug concentration profile required to elicit the desired therapeutic effect
whereas pharmacokinetics determines the drug dosing regimen necessary to achieve the targeted drug
concentrations. As in pharmacokinetics, methods to measure pharmacologic effects and biomath-
ematical models had to be developed for characterizing and evaluating pharmacodynamic processes,
i.e., the time courses of various pharmacologic effects. The models serve to summarize by means of
appropriate parameter values the pharmacodynamic process(es) under consideration. The
pharmacodynamic parameter values are used to assess the possible influence of such variables as age,
gender, race, concomitant or prior use of other drugs, and disease on the drug concentration versus
effect relationship. A combination of pharmacokinetic-pharmacodynamic models should be able to
permit predictions of the effects of dose, dosing rate, and time on the temporal pattern of drug effects.
A proper analysis of drug effect-concentration-time data can lead to the recognition of possible
functional tolerance development or the formation of pharmacologically active or interactive metabo-
lites. It can rationalize an apparent dissociation between the time courses of drug concentration and
effect on the basis of drug distribution to an apparent effect compartment or as a consequence of an
indirect mechanism of action of the drug.
Since pharmacokinetic (PK) and pharmacodynamic (PD) processes are so intimately associated
as determinants of the time course of pharmacologic effects, it is customary to perform combined
pharmacokinetic-pharmacodynamic modeling rather than to simply characterize drug concentration-
effect relationships in isolation. PK-PD modeling, like pharmacokinetic modeling, requires a certain
research discipline: one initially develops a model based, if possible, on the known mechanism of the
drug’s action and on available concentration-effect-time data; one then verifies and refines (or
replaces) the model by additional studies with different single and multiple bolus doses or different
rates of intravenous infusion. To distinguish between several possible models, one uses computer
simulations to determine the experimental conditions that can best reveal the most appropriate model.
Unfortunately, this kind of research discipline is not yet well developed in pharmacodynamics; there
have been many “hit-and-run” types of study consisting of pharmacodynamic modeling of single dose
concentration-effect-time data without appropriate verification. As in pharmacokinetics, such mind-
less number crunching will gradually diminish and eventually disappear as the science of
pharmacodynamics matures.
Many pharmacodynamic studies are performed by measuring surrogate effects, i.e., effects that
are believed to directly reflect the therapeutic (or toxic) effects of interest but are more easily measured
than the therapeutic effects. It is tempting for the kineticist to measure and model that which is most
readily measurable even if it is not that which is most relevant to the clinical use of a drug. The use
of surrogate measures of drug effects in research and product development is presently the subject of
intensive debate; it has practical, ethical, financial, and political aspects. From a scientific perspective,
the suitability of surrogate markers of drug effects should be assessed on the basis of the biochemical
or physiological mechanisms involved and the locus of drug action. In the final analysis, long-term
studies at different and relatively constant drug concentrations may be required to characterize the
pharmacodynamics of certain therapeutic effects (for example, the effect of an antihypertensive agent
on morbidity and mortality).
It is already evident that there are quantitative interindividual differences in the pharmacodynamics
of many drugs, associated with such variables as age, gender, race, and disease. Much effort will have
to be directed in the future to the study of population pharmacodynamics in the hope of discovering
useful covariates or predictors of an individual’s pharmacodynamic characteristics. Such studies must
be designed in accordance with the relevant epidemiologic principles so that they encompass a patient
population in which all possible important covariates (demographic and pathophysiologic variables)
are adequately represented. The results of such population pharmacodynamic studies, together with
corresponding population pharmacokinetic information, will constitute the basis for the “software” or
“user’s manual” that should be developed for every new drug to instruct physicians and pharmacists
how to optimize the dosage regimen for individual patients.
A book on pharmacodynamics can emphasize theory, applications, or both. This book strikes an
effective balance between theory and practice, with the first four chapters devoted to the general
principles of PK-PD modeling and the twelve subsequent chapters focusing on specific classes of
medicinal agents. This will permit the reader to visualize the translation of theory to practice and,
hopefully, encourage him/her to apply the principles of pharmacodynamics in rational drug product
development and pharmacotherapy.
Gerhard Levy
Department of Pharmaceutics
School of Pharmacy
State University of New York at Buffalo
The Editors
Hartmut Derendorf, Ph.D., is Professor and Chairman of the Department of Pharmaceutics in
the College of Pharmacy, University of Florida in Gainesville, Florida.
Dr. Derendorf received his B.S. (1976) and Ph.D. (1979, summa cum laude) in Pharmacy from
the University of Münster, Germany and then joined the University of Florida, first as a Postdoctoral
Fellow (1981/1982) and later (1983) as afaculty member. In 1987 he was appointed Chairman of the
Department of Pharmaceutics. He has been teaching Biopharmaceutics, Pharmacokinetics, and
Clinical Pharmacokinetics at the University of Florida since 1983. He also was the instructor of more
than 15 courses on pharmacokinetics in the U.S., Germany, England, and Brazil.
Dr. Derendorf is a member of the American Association of Pharmaceutical Scientists, American
College of Clinical Pharmacology, American Pharmaceutical Association, Florida Pharmacy Asso-
ciation, German Pharmaceutical Society, American Society for Clinical Pharmacology and Therapeu-
tics, American Association of Colleges of Pharmacy, American Association for the Advancement of
Science, and a founding member of the European Society for Biomodulation and Chemotherapy. In
1988, he was elected Fellow of the American College of Clinical Pharmacology, and, at present, serves
on the Board of Regents of this organization.
Dr. Derendorf has published over 110 scientific publications and given over 200 presentations at
national or international meetings. He has authored four textbooks in English and German. His
research interests include the pharmacokinetics and pharmacodynamics of corticosteroids, analgesics,
and antibiotics.
Gunther Hochhaus, Ph.D., is Associate Professor of the Department of Pharmaceutics in the
College of Pharmacy, University of Florida in Gainesville, Florida.
Dr. Hochhaus received his B.S. (1979) and Ph.D. (1984) from the University of Munster,
Germany. He then joined as a Postdoctoral Research Pharmacologist in the Department of Pharma-
ceutical Chemistry, School of Pharmacy, University of California, San Francisco, working for
Professor W. Sadee. He was appointed Assistant Professor in the Department of Pharmaceutics,
College of Pharmacy, University of Florida in July 1987. In July 1992, Dr. Hochhaus was promoted
to the position of Associate Professor. He is responsible for pharmaceutical analysis courses on the
undergraduate and graduate level, currently responsible for the Biopharmaceutics and Pharmacoki-
netic class in the Department of Pharmaceutics, University of Florida, Gainesville.
Dr. Hochhaus received the “Young Investigator Award” from the Deutsche Gesellschaft fuer
Atemwegs und Lungenforschung for the pharmacokinetic/dynamic properties of fenoterol, and was
elected Fellow of the American College of Clinical Pharmacology.
Dr. Hochhaus is a member of the American Association of Pharmaceutical Scientists, the
American Association for the Advancement of Science, and the American College of Clinical
Pharmacology. He has published over 50 articles in prestigious scientific journals. His research
interests include glucocorticoid receptor pharmacology, pharmacokinetic/dynamic evaluation of drug
action, and peptide analysis and metabolism.
Contributors
Stefan Balbach William E. Evans
College of Pharmacy University of Florida Pharmaceutical Department
Gainesville, Florida St. Jude Children’s Research Hospital
Center for Pediatric Pharmacokinetics
Jürgen Barth and Therapeutics
Medical Clinic “Bergmannsheil” Departments of Clinical Pharmacy
University of Bochum and Pediatrics
Bochum, Germany University of Tennessee
Memphis, Tennessee
Meindert Danhof
James J. Ferry
Leiden-Amsterdam Center for Drug
Research Clinical Pharmacokinetics Unit
Department of Pharmacology The Upjohn Company
Sylvius Laboratory Kalamazoo, Michigan
Leiden, The Netherlands
Joseph C. Fleishaker
Clinical Pharmacokinetics Unit
Hartmut Derendorf
The Upjohn Company
College of Pharmacy University of
Kalamazoo, Michigan
Florida
Gainesville, Florida
Ho-Leung Fung
Department of Pharmaceutics
Steven C. Ebert
School of Pharmacy State University
Infectious Diseases/Pharmacokinetics
of New York
Department of Pharmacy
Buffalo, New York
Meriter Hospital
Clinical Associate Professor
Samir K. Gupta
School of Pharmacy University of
Department of Clinical Pharmacology
Wisconsin
Glaxo Research Institute
Madison, Wisconsin
R.T.P., North Carolina
Everett H. Ellinwood Joe Heissler
Department of Psychiatry Clinical Pharmacokinetics Services
Duke University Bronson Memorial Hospital
Durham, North Carolina Kalamazoo, Michigan
Jos Heykants Arno Nolting
Department of Drug Metabolism and College of Pharmacy University of
Pharmacokinetics Florida
Janssen Research Foundation Gainesville, Florida
Beerse, Belgium
Virginia D. Schmith
Günther Hochhaus Department of Clinical Pharmacokinetics/
College of Pharmacy University of Dynamics
Florida Burroughs Wellcome Company
Gainesville, Florida Research Triangle Park, North Carolina
Mattieu Kaltenbach Eric Snoeck
Université de Reims Department of Drug Metabolism
Faculté de Pharmaci and Pharmacokinetics
Reims, France Janssen Research Foundation
Beerse, Belgium
Richard L. Lalonde
Pharmacokinetics and Clinical Tsang-Bin Tzeng
Pharmacology Department of Pharmaceutical Sciences
Phoenix International Life Sciences Inc. Temple University
St. Laurent, Quebec, Canada Philadelphia, Pennsylvania
Howard L. McLeod Achiei Van Peer
CRC Department of Medical Oncology Department of Drug Metabolism
University of Glasgow and Pharmacokinetics
Glasgow, Scotland Janssen Research Foundation
Beerse, Belgium
Helmut Möllmann
Jürgen Venitz
Medizinische Universitätsklinik und
Department of Pharmacy and
Poliklinik“Bergmannsheir der
Pharmaceutics
Ruhruniversität Bochum
Medical College of Virginia/Virginia
Bochum, Germany
Commonwealth University
Richmond, Virginia
Keith T. Muir
Clinical Pharmacokinetics
Rob A. Voskuyl
Department of Clinical Pharmacology
Instituut voor Epilepsiebestrijding
Glaxo, Inc.
‘Meer en Bosch - de Cruquiushoeve’
Research Triangle Park, North Carolina
Heemstede, The Netherlands
Department of Physiology
Dennis Mungall Faculty of Medicine
Therapeutic Technologies, Inc. University of Leiden
Tallahassee, Florida Leiden, The Netherlands
