Clinical Pharmacokinetics and Pharmacodynamics

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  • Clinical Pharmacokineticsand PharmacodynamicsC O N C E P T S A N D A P P L I C A T I O N S

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  • Clinical Pharmacokineticsand PharmacodynamicsC o n c e p t s a n d A p p l i c a t i o n s

    Malcolm Rowland, DSc, PhDProfessor EmeritusSchool of Pharmacy and

    Pharmaceutical SciencesUniversity of ManchesterManchester, United Kingdom

    F O U R T H E D I T I O N

    Thomas N. Tozer, PharmD, PhDProfessor EmeritusSchool of Pharmacy and

    Pharmaceutical SciencesUniversity of California, San FranciscoAdjunct Professor of PharmacologySkaggs School of Pharmacy and

    Pharmaceutical SciencesUniversity of California San Diego

    With Online Simulations byHartmut Derendorf, PhDDistinguished ProfessorGuenther Hochhaus, PhDAssociate ProfessorDepartment of PharmaceuticsUniversity of FloridaGainesville, Florida

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  • Acquisitions Editor: David B. TroyProduct Manager: Matt HauberMarketing Manager: Allison PowellDesigner: Doug SmockCompositor: Maryland Composition Inc./ASI

    Fourth Edition

    Copyright 2011 Lippincott Williams & Wilkins, a Wolters Kluwer business351 West Camden Street 530 Walnut StreetBaltimore, MD 21201 Philadelphia, PA 19106

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    Library of Congress Cataloging-in-Publication Data

    Rowland, Malcolm.Clinical pharmacokinetics and pharmacodynamics : concepts and applications / Malcolm

    Rowland and Thomas N. Tozer. 4th ed.p. ; cm.

    Rev. ed. of: Clinical pharmacokinetics. 1995.ISBN 978-0-7817-5009-71. Pharmacokinetics. 2. Chemotherapy. I. Tozer, Thomas N. II. Rowland, Malcolm. Clinical phar-

    macokinetics. III. Title.[DNLM: 1. Pharmacokinetics. 2. Drug Therapy. QV 38 R883c 2009]RM301.5.R68 2009615.7dc22



    Care has been taken to confirm the accuracy of the information present and to describe gener-ally accepted practices. However, the authors, editors, and publisher are not responsible for errorsor omissions or for any consequences from application of the information in this book and makeno warranty, expressed or implied, with respect to the currency, completeness, or accuracy of thecontents of the publication. Application of this information in a particular situation remains theprofessional responsibility of the practitioner; the clinical treatments described and recommendedmay not be considered absolute and universal recommendations.

    The authors, editors, and publisher have exerted every effort to ensure that drug selection anddosage set forth in this text are in accordance with the current recommendations and practice atthe time of publication. However, in view of ongoing research, changes in government regulations,and the constant flow of information relating to drug therapy and drug reactions, the reader isurged to check the package insert for each drug for any change in indications and dosage and foradded warnings and precautions. This is particularly important when the recommended agent is anew or infrequently employed drug.

    Some drugs and medical devices presented in this publication have Food and DrugAdministration (FDA) clearance for limited use in restricted research settings. It is the responsibil-ity of the health care provider to ascertain the FDA status of each drug or device planned for usein their clinical practice.

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  • To Dawn and Margaretfor their continual love, patience, and tolerance.

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  • MALCOLM ROWLANDMalcolm Rowland is Professor Emeritus and former Dean(19982001), School of Pharmacy and Pharmaceutical Sciences,University of Manchester, and Adjunct Professor, School ofPharmacy, University of California, San Francisco. He wasPresident of the European Federation of Pharmaceutical Sciences(19962000) and Vice-President, International PharmaceuticalFederation (FIP; 20012008), the organization that representsand serves pharmacy and pharmaceutical sciences around theglobe. He received his pharmacy degree and PhD from the

    University of London, and was on faculty at the School of Pharmacy, University ofCalifornia, San Francisco (19671975).

    Dr. Rowland, together with Dr. Thomas Tozer, authored the introductory textbook,Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of DrugTherapy. He has authored over 300 scientific articles and chapters. His research interest isprimarily in physiologically-based pharmacokinetics and its application to drug develop-ment and clinical use. In particular, he has pioneered the concept and application ofclearance and developed approaches to the prediction of pharmacokinetics of drugsfrom a combination of physicochemical properties and in vitro information. He was aneditor of the Journal of Pharmacokinetics and Pharmacodynamics (19732006), the pre-mier journal dedicated to the subject, and has established workshops for teaching bothbasic- and advanced-level pharmacokinetics. He is an advisor to the pharmaceuticalindustry and sits on various scientific advisory boards.

    Dr. Rowland has been awarded honorary doctorate degrees from the University ofPoitiers (France) and Uppsala University (Sweden) as well as Honorary Membership ofthe Royal College of Physicians (London). He received various awards including theDistinguished Investigator Award of the American College of Clinical Pharmacology(ACCP, 2007) and the Millennial Pharmaceutical Scientist Award (FIP BPS, 2000). Hehas been made a fellow of the Academy of Medical Sciences, ACCP (Hon), AmericanAssociation of Pharmaceutical Scientists, the Royal Pharmaceutical Society of GreatBritain, and the Institute of Mathematics.

    THOMAS N. TOZERDr. Tozer, Professor Emeritus of Biopharmaceutical Sciences andPharmaceutical Chemistry, School of Pharmacy, University ofCalifornia, San Francisco, received his BS, PharmD, and PhD de-grees from the University of California, San Francisco. He is cur-rently an Adjunct Professor of Pharmacology at the University ofCalifornia, San Diego, where he teaches biopharmaceutics andclinical pharmacokinetics at the Skaggs School of Pharmacy andPharmaceutical Sciences. After a 2-year postdoctoral fellowship inthe laboratory of Dr. B. B. Brodie, National Institutes of Health,



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  • Bethesda, Maryland, he joined the Faculty of the School of Pharmacy in San Francisco in1965. Although now in emeritus status, he continues to teach courses and workshops inpharmacokinetics/pharmacodynamics and clinical pharmacokinetics at several institu-tions in the United States and Europe.

    Dr. Tozer, together with Dr. Malcolm Rowland, authored Clinical Pharmacokinetics:Concepts and Applications, the title of the first three editions of this textbook. He has pub-lished more than 155 scientific papers on a variety of research topics with emphasis onthe development and application of kinetic concepts in drug therapy. Dr. Tozersresearch before retirement was focused in four areas: colon-specific drug delivery, toxico-kinetics, kinetics of potential contrast agents for magnetic resonance imaging, and non-linear pharmacokinetics. Other research included determination of drug disposition indisease states, particularly end-state renal disease. Emphasis here was placed on evaluat-ing and predicting when and how drug administration to renal disease patients shouldbe altered.

    Dr. Tozer was a corecipient of the 2000 Meritorious Manuscript Award, AmericanAssociation of Pharmaceutical Scientists, and was a Visiting Professor (19961999) at theUniversity of Manchester, Manchester, England. He is a Fellow of the AmericanAssociation of Pharmaceutical Scientists and has served as a consultant to the Food andDrug Administration and to many pharmaceutical companies.


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  • uch has happened in the field of our textbook since the last edition was publishedin 1995. First, in recognition that there was a readership that sought a less in-depthtextbook we wrote a companion, entitled Introduction to Pharmacokinetics and

    Pharmacodynamics: The Quantitative Basis of Drug Therapy; it was published in 2006. While em-phasizing pharmacokinetics, the widening to include pharmacodynamics as an integralpart of this introductory text reflected the increasing body of knowledge linking the two el-ements that explain the relationship between drug administration and response. We havecontinued this trend of integrating pharmacodynamics with pharmacokinetics in the cur-rent text, which is reflected in the ti