Handbook of Pharmacokinetic/Pharmacodynamic Correlation PDF
Preview Handbook of Pharmacokinetic/Pharmacodynamic Correlation
Handbook 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 CRC Press is an imprint of the Taylor & Francis Group, an informa business CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 Reissued 2019 by CRC Press © 1995 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. A Library of Congress record exists under LC control number: Publisher's Note The publisher has gone to great lengths to ensure the quality of this reprint but points out that some imperfections in the original copies may be apparent. Disclaimer The publisher has made every effort to trace copyright holders and welcomes correspondence from those they have been unable to contact. ISBN 13: 978-0-367-22803-3 (hbk) ISBN 13: 978-0-367-22808-8 (pbk) ISBN 13: 978-0-429-27696-5 (ebk) Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com 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
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