CONCEPTS IN CLINICAL
PHARMACOKINETICS - 4th Ed. (2005)
Concepts in Clinical Pharmacokinetics
Joseph T. DiPiro Pharm.D. Professor and Executive Dean, South Carolina College of Pharmacy, The University of South Carolina, Columbia, Medical University of South Carolina, Charleston, South Carolina
William J. Spruill Pharm.D., FASHP Professor, Department of Clinical and Administrative Pharmacy at the University of Georgia College of Pharmacy, Athens, Georgia
William E. Wade Pharm.D., FASHP Professor, Department of Clinical and Administrative Pharmacy at the University of Georgia College of Pharmacy, Athens, Georgia
Robert A. Blouin Pharm.D. Professor and Dean, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Jane M. Pruemer Pharm.D., BCOP Associate Professor of Clinical Pharmacy Practice, University of Cincinnati College of Pharmacy, Cincinnati, Ohio
American Society of Health-System Pharmacists
Any correspondence regarding this publication should be sent to the publisher, American Society of Health-System Pharmacists, 7272 Wisconsin Avenue, Bethesda, MD 20814, attn: Special Publishing. Produced in conjunction with the ASHP Publications Production Center.
The information presented herein reflects the opinions of the contributors and reviewers. It should not be interpreted as an official policy of ASHP or as an endorsement of any product.
Drug information and its applications are constantly evolving because of ongoing research and clinical experience and are often subject to professional judgment and interpretation by the practitioner and to the uniqueness of a clinical situation. The editors, authors, and ASHP have made every effort to ensure the accuracy and completeness of the information presented in this book. However, the reader is advised that the publisher, author, contributors, editors, and reviewers cannot be responsible for the continued currency or accuracy of the information, for any errors or omissions, and/or for any consequences arising from the use of the information in the clinical setting.
The reader is cautioned that ASHP makes no representation, guarantee, or warranty, express or implied, that the use of the information contained in this book will prevent problems with insurers and will bear no responsibility or liability for the results or consequences of its use.
Acquisition Editor: Hal Pollard Managing/Development Editor: Dana Battaglia Production: Silverchair Science + Communications, Inc.
Library of Congress Cataloging-in-Publication Data Concepts in clinical pharmacokinetics / Joseph T. DiPiro ... [et al.]. - 4th ed. p. ; cm. -- Includes bibliographical references and index. ISBN 1-58528-124-7 1. Pharmacokinetics. [DNLM: 1.
PharmacokineticsProgrammed Instruction. 2. Pharmaceutical Preparations-- administration &
dosageProgrammed Instruction. QV 18.2 C744 2005] I. Title: Clinical pharmacokinetics. II. DiPiro, Joseph T. III. American Society of Health-System Pharmacists RM301.5.C66 2005 615'.7--dc22 2005011225
2005, American Society of Health-System Pharmacists, Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without written permission from the American Society of Health-System Pharmacists.
ASHP is a service mark of the American Society of Health-System Pharmacists, Inc.; registered in the U.S. Patent and Trademark Office.
ISBN-13: 978-1-58528-124-4 ISBN-10: 1-58528-124-7
Preface to the Third Edition ix
Preface to the Fourth Edition xi
Pharmacy Continuing Education Program xv
Lessons and Practice Sets
Lesson 1. Introduction to Pharmacokinetics and Pharmacodynamics 1
Lesson 2. Basic Pharmacokinetics 19
Lesson 3. Half-Life, Elimination Rate, and AUC 29
Practice Set 1 43 Lesson 4. Intravenous Bolus Administration, Multiple Drug Administration, and Steady-State
Average Concentrations 45 Lesson 5. Relationships of Pharmacokinetic Parameters and Intravenous Intermittent and
Continuous Infusions 59
Lesson 6. Two-Compartment Models 73
Practice Set 2 83
Lesson 7. Biopharmaceutics: Absorption 87
Lesson 8. Drug Distribution and Protein Binding 101
Lesson 9. Drug Elimination Processes 111
Lesson 10. Nonlinear Processes 129
Lesson 11. Pharmacokinetic Variation and Model-Independent Relationships 139
Practice Set 3 153
Lesson 12. Aminoglycosides 157
Lesson 13. Vancomycin 173
Lesson 14. Theophylline 187
Lesson 15. Phenytoin and Digoxin 193
Appendix A. Basic and Drug-Specific Pharmacokinetic Equations 203
Appendix B. Supplemental Problems 211
Appendix C. Glossary 217
The authors are indebted to George Francisco, Kim Brouwer, Stan Greene, Cecily DiPiro, William H. Asbury, Maureen S. Boro, W. Greg Leader, Daniel Maddix, Gary R. Matzke, Page H. Pigg, Carl Possidente, and John R. Reynolds for their review and suggestions during the preparation of the first and second editions. The third and fourth editions reflect the suggestions of many individuals who used the manual and recommended improvements. The rigorous effort and valuable suggestions provided by Dana Battaglia for this edition are greatly appreciated.
Preface to the Third Edition
This programmed manual presents basic pharmacokinetic concepts and procedures that are useful in pharmacy, medicine, and other health professions. Most of the material relates to individualization
of drug dosing regimens. Although this text is not intended to create a practitioner fully competent in clinical pharmacokinetics, it will provide an orientation to the concepts involved.
After completing this text, the reader should be prepared to begin learning the pharmacokinetic techniques for clinical situations. The reader should participate in structured educational settings, such as a formal clinical pharmacokinetics course or a clerkship under an experienced clinical practitioner, to develop clinical skills related to pharmacokinetics. Readers who want in-depth understanding of the derivations of pharmacokinetic equations should consult an appropriate text.
In this third edition, the manual is divided into 15 lessons to allow progression on a typical semester schedule of 15 weeks. The first 11 lessons include pharmacokinetic and pharmacodynamic principles as well as an overview of biopharmaceutic principles. Each of these lessons begins with a list of educational objectives and concludes with a series of questions. Answers and feedback for incorrect responses have been provided for the short-answer questions. Discussion questions have been added. Lessons 12 through 15 present brief patient case studies with aminoglycosides, theophylline, vancomycin, digoxin, and phenytoin so the reader can practice the use of pharmacokinetic equations.
This edition will be accompanied by a Web-based version that will provide lessons to parallel each of the lessons in the print version. The Web-based version will include dynamic figures and simulators, calculators for applying pharmacokinetic equations, links to important Web pages, and interactive capability for discussion questions. Although the print version may be used independently, we believe that concurrent use of both versions will enhance learning.
Joseph T. DiPiro William J. Spruill Robert A. Blouin Jane M. Pruemer
Preface to the Fourth Edition
Although the fourth edition of Concepts in Clinical Pharmacokinetics continues to provide basic pharmacokinetic concepts and procedures that are useful in pharmacy, medicine, and other health professions, this new edition has been revised to be, we anticipate, even more instructive and user-friendly for the reader.
All of the chapters are revised, with many new clinical correlates and some new figures. All similar equations are cross-referenced throughout the book to allow the student to compare the various equations. All cases are revised and new ones added. A new appendix, Basic and Drug-Specific Pharmacokinetic Equations, summarizes and lists all equations needed to dose selected drugs (aminoglycoside, vancomycin, theophylline, digoxin, and phenytoin). In addition, more in-depth answers and feedback for incorrect responses are provided for the short-answer questions.
Overall, this edition looks different as well. Figures are larger and equations clearer. All features are designated with specific design elements for easy navigation throughout the chapters. Our goal is to provide the student with an optimum learning experience. We hope this new design and the other enhancements help to achieve that goal.
Joseph T. DiPiro William J. Spruill William E. Wade Robert A. Blouin Jane M. Pruemer
: distribution rate constant for two-compartment model AUC : area under plasma drug concentration versus time curve
AUMC : area under the (drug concentration time) versus time (moment) curve
: terminal elimination rate constant C : concentration
: average steady-state concentration C0, C1, C2 : initial (just after infusion), first, second concentrations Cin : concentration in blood on entering organ Clast : last measured concentration Cmax : maximum concentration Cmax1, Cmax2 : first, second maximum concentrations