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`FOURTH EDITION
`
`Clinical Pharmacokinetics
`and Pharmacodynamics
`
`Concepts and Applications
`
`Malcolm Rowland, Dsc. PhD Thomas N. Tozer, PharmD, PhD
`
`Professor Emeritus
`School of Pharmacy and
`Pharmaceutical Sciences
`University of Manchester
`Manchester, United Kingdom
`
`Professor Emeritus
`School of Pharmacy and
`Pharmaceutical Sciences
`University of California, San Francisco
`Adjunct Professor of Pharmacology
`Skaggs School of Pharmacy and
`Pharmaceutical Sciences
`University of California San Diego
`
`With Online Simulations by
`Hartmut Derendorf, PhD
`Distinguished Professor
`Guenther Hochhaus, PhD
`Associate Professor
`Department of Phannaceuti cs
`University of Florida
`Gainesville, Florida
`
`®.Wolters Kluwer I Lippincott Williams & Wilkins
`
`Healt h
`Philadelphia • Baltimore • New York • London
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`IPR2018-00943
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`Acquisitions Editor: David B. Troy
`Product Manager: Matt Hauber
`Marketing Manager: Allison Powell
`Designer: Doug Smock
`Compositor: Maryland Com position Inc./ ASI
`Fourth Edition
`Copyright© 2011 Lippincott Williams & Wilkins, a Wolters Kluwer business
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`Baltimore, MD 21201
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`Printed in China
`All rights reserved. This book is protected by copyright. No part of this book may be reproduced or
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`9 8 7 6 5 4 3 2 1
`Library of Congress Cataloging-in-Publication Data
`Rowland, Malcolm.
`Clinical pharmacokinetics and pharmacodynamics
`Rowland and Thomas N. Tozer. -4th ed.
`p.; em.
`Rev. ed. of: Clinical pharmacokinetics. 1995.
`ISBN 978-0-7817-5009-7
`1. Pharmacokinetics. 2. Chemotherapy. I. Tozer, Thomas N. II. Rowland, Malcolm. Clirucal phar-
`macokinetics. III. Title.
`[DNLM: l. Pharmacokinetics. 2. Drug Therapy. QV 38 R883c 2009]
`RM301.5.R68 2009
`615'.7-dc22
`
`concepts and applications I Malcolm
`
`2009028928
`
`DISCLAIMER
`Care has been taken to confirm the accuracy of the information present and to describe gener-
`ally accepted practices. However, the authors, em tors, and publisher are not responsible for errors
`or omissions or for any consequences from application of the information in this book and make
`no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the
`contents of the publication. Application of this information in a particular situation remains the
`professional responsibility of the practitioner; the clinical treatments described and recommended
`may not be considered absolute and universal recommendations.
`The authors, editors, and publisher have exerted every effort to ensure that drug selection and
`dosage set forth in this text are in accordance with the current recommendations and practice at
`the 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 is
`urged to check the package insert for each drug for any change in indications and dosage and for
`added warnings and precautions. Tills is particularly important when the recommended agent is a
`new or infrequently employed drug.
`Some drugs and medical devices presented in this publication have Food and Drug
`Administration (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 use
`in their clinical practice.
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`en
`~ ,....
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`
`AMN1089
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`

`

`•
`
`SECTION I I Basic Considerations
`
`Another very important factor is the maximum effect of the drug. That is, the great-
`est possible effect, Emax, that can be achieved with the compound. Returning to the exam-
`ple of ketamine, it is apparent that however high we increase the concentration of R(- )-
`ketarnine, we can never achieve the same maximum response as can be achieved with the
`S( +)-isomer. Clearly, if the desired therapeutic response demands that the effect be
`greater than can be achieved with R(- )-ketamine, then no matter how potent this com-
`pound, it would be of little therapeutic value when given alone. The last important phar-
`macodynamic factor for a graded response is the steepness factor, 'Y· If it is very high, it
`may be difficult to manage the use of the drug as only a small shift in concentration
`around the C50 causes the response to change from zero to full effect, and vice versa. In
`contrast, if the value of 'Y is very small, then large changes in drug concentration are
`needed to cause the respo nse to change significantly, particularly beyond the C50 value.
`Clearly, a value between these two extremes is desirable.
`
`DOSE-TIME-RESPONSE RELATIONSHIPS
`So far, relationships between dose and measures of drug exposure and between response
`and exposure have been explored. In clinical practice, decisions have to be made as to
`the dosage regimen to employ to ensure optimal benefit within the confines of the con-
`ditions in which the patient receives a drug. This is a complex decision involving consid-
`eration of many factors including not only the pharmacokinetics and pharmacodynamics
`of the drug, but also the nature of the disease being treated, as well as a host of patient
`factors, both clinical and social. Some of these aspects are considered in the remainder
`of the book. H owever, at this point some broad issues, centered on exposure-response
`relationships, are worth considering.
`Drugs are given to achieve therapeutic objectives; the practical question is how best to
`do so? One approach is to examine the pharmacokinetics of a drug. Figure 2-18 contains
`typical plots of plasma drug concentration witl1 time following oral administration of a
`single dose. One may then ask: What feature of the exposure profile is m ost important in
`the context of the desired therapeutic objective? In Fig. 2-18A are displayed the concen-
`tration-time profiles for two drugs achieving the same maximum concentration ( Cmax)
`and the same time to reach Cmax ( t,rulX) but differing in tl1e kinetics of decline in their con-
`centrations beyond the peak. For some drugs intended to be given chronically, it is only
`importan t to maintain the plasma concentration above a defined minimum, below which
`100
`~ 80
`C) ::::I.
`.... c:
`::~-- 60
`Co
`cu-:;:; E !!! 40
`1/)-
`as c:
`-GI
`Q..CJ 20
`c:
`0
`(.)
`
`100
`
`0
`
`12
`
`36
`
`48
`
`24
`24
`A
`Hours
`B
`Hours
`FIGURE 2-18. Schematic representations of the plasma concentration-time profiles following a
`single oral dose. A. For two drugs that produce similar peak concentrations and time to peak, but one
`(colored line) declines more slowly than the other thereby creating a greater total exposure (AUG)
`and higher concentrations at later times. B. For a drug that produces the same total AUG when given
`on two occasions, but on one of these occasions (colored line) the peak concentration is lower and
`later due to a slowing of absorption.
`
`--...J a, 80
`C) ::::I.
`.... c 60
`::~--
`0 0
`Cll~ E_ 40
`1/) c:
`..!!! Q)
`a.. (J
`c
`20
`0
`(.)
`0
`
`0
`
`12
`
`36
`
`48
`
`AMN1089
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`