Clinical Pharmacokinetics
`Concepts and Applications
`
`third edition (cid:9)
`
`1
`
`ATI 1034-0001
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`ATI v. ICOS
`IPR2018-01183
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`

`

`AI&
`
`Executive Editor Donna Balado
`Developmental Editors: Frances Klass, Lisa Stead
`Production Manager: Laurie Forsyth
`Project Editor. Robert D. Magee
`
`Copyright @ 1995
`Lippincott Williams & Wilkins
`530 Walnut Street
`Philadelphia, Pennsylvania 19106-3621 USA
`
`All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any
`form or by any means, including photocopying, or utilized by any information storage and retrieval system
`without written permission from the copyright owner.
`
`Accurate indications, adverse reactions, and dosage schedules for drugs are provided in this book, but it is
`possible they may change. The reader is urged to review the package information data of the manufacturers
`of the medications mentioned.
`
`Printed in the United States of America
`
`First Edition 1980
`
`Library of Congress Cataloging-in-Publication Data
`
`Rowland, Malcolm.
`Clinical Pharmacokinetics : concepts and applications / Malcolm
`Rowland, Thomas N. Tozer. — 3rd ed.
`p. (cid:9)
`cm.
`"A Lea & Febiger Book."
`Includes bibliographical references and index.
`ISBN 978-0-683-07404-8
`ISBN 0-683-07404-0
`1. Pharmacokinetics. 2. Chemotherapy. (cid:9)
`II. Title.
`[DNLM: 1. Pharmacokinetics. 2. Drug Therapy. (cid:9)
`RM301.5.R68 (cid:9)
`1994
`615.7—dc20
`DNLM/DLC
`for Library of Congress
`
`I. Tozer, Thomas N.
`
`QV 38 R883c 19941
`
`94-26305
`CIP
`
`The Publishers have made every effort to trace the copyright holders for borrowed material. If they have in-
`advertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity.
`
`13 14 15 16 17 18 19 20
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`ATI 1034-0002
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`PHARMACOLOGIC RESPONSE
`
`OBJECTIVES
`The reader will be able to:
`1 . Describe, with examples, the relationship generally expected between a graded response
`and concentration at the site of action.
`2. Show graphically how one can readily detect when response is delayed compared to
`plasma drug concentration after a single dose, and give at least two explanations for the
`delay.
`3. Describe the parameters of the model that often characterize the relationship between re-
`sponse and plasma concentration.
`4. Explain why duration of response is often proportional to the logarithm of an intravenously
`administered dose, and when it is, calculate both the minimum effective dose and the
`effective half-life.
`5. Describe the influence of distribution kinetics on the relationship between duration of re-
`sponse and logarithm of the dose following single i.v. boluses.
`6. Show graphically how duration and intensity of response change on repetitive dosing when
`each dose is given just as the response and concentration fall to predetermined levels for
`drugs showing one- or two-compartment distribution characteristics.
`7. Show why response of reversibly acting drugs declines linearly with time when response is
`proportional to the logarithm of the concentration and concentration declines exponentially.
`
`The basic principles surrounding the establishment of an appropriate dosage regimen are
`presented in Chap. 5. These principles rest heavily on there being a functional relationship,
`albeit sometimes complex, between concentration of drug at site(s) of action and response
`produced. Some evidence supporting this view is presented in Chap. 5, together with short
`commentaries on such additional considerations as delays in drug response, role of active
`metabolites, and tolerance. In this chapter some of these aspects are considered in greater
`depth and the temporal relationship between dose (or concentration) and response is ex-
`plored. The chapter begins with an examination of the concentration—response relationship
`and concludes with a discussion of hysteresis in a plot of response versus concentration.
`
`CONCENTRATION AND RESPONSE
`Because sites of action lie mostly outside the vasculature, delays often exist between place-
`ment of drug into blood and response produced. Such delays can obscure underlying re-
`lationships between concentration and response. One potential solution is to measure con-
`centration at the site of action. Although this may be possible in an isolated organ system,
`it is rarely a practical solution in humans. Apart from ethical and technical issues that arise,
`
`ATI 1034-0003
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`CHAPTER 20
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`PHARMACOLOGIC RESPONSE (cid:9)
`
`341
`
`many responses observed in vivo represent an integration of multiple effects at numerous
`sites. Another approach is to develop a model that incorporates the time-course of drug
`movement between plasma and site of action, thereby predicting "effector site" concen-
`trations that can then be related to response. Yet another approach is to relate plasma
`concentration to response under steady-state conditions, which obviates consideration of
`distribution kinetics. Whatever the approach adopted, the resulting concentration—response
`relationships for most drugs have features in common. Response increases with concen-
`tration at low concentrations and tends to approach a maximum at high values. Recall from
`Chap. 5 that this was observed for the bronchodilating effect of terbutaline. Such an effect
`is also seen for the anesthetic ketamine, as illustrated in Fig. 20-1. R( — )-ketamine and
`S( + )-ketamine are optical isomers which, as the racemate, constitute the commercially
`available intravenous (i.v.) anesthetic agent, ketamine. Although both compounds have an
`anesthetic effect, they clearly differ from each other. Not only is the maximum effect (E )
`with R( — )-ketamine less than that with S( + )-ketamine, but the plasma concentration
`required to produce 50% of E , referred to as the EC 50 value, is also greater (1.8 mg/L
`versus 0.7 mg/L). Moreover, the response curve for R( — )-ketamine appears shallower than
`that for S( + )-ketamine. Although the reason for the differences are unclear, these obser-
`vations stress the importance that stereochemistry can have in drug response.
`
`General Equation
`
`A general equation to describe the types of observations seen in Figs. 5-1 and 20-1 is
`
`E (cid:9)
`Intensity of Effect — EC1 m'x
`0
`
`•
`CY
`+
`
`1
`
`where E
`and EC50 are as defined above and 7 is the shape factor that accommodates the
`shape of the curve. The intensity of response is usually a change in a measurement from its
`basal value expressed as either an absolute difference, or a percent change. Examples are an
`increase in blood pressure and a decrease in percent of neuromuscular blockade.
`Although empirical, Eq. 1 has found wide application. Certainly, it has the right prop-
`erties. Fig. 20-2A shows the influence of 7 on the shape of the concentration—response
`relationship. The larger the value of 'y, the greater is the change in response with concen-
`
`2 100
`a)
`cr a)
`
`75
`
`Co
`
`50
`
`25
`
`0
`
`cc
`0
`a) U
`
`aJ
`
`S(+)-Ketamine
`
`EC5 0
`
`MO
`
`R(—)-Ketamine E
` max
`
`1
`E max
`
`3 (cid:9)
`2 (cid:9)
`1 (cid:9)
`4
`Plasma Concentration (mg/L)
`
`Fig. 20.-1. Changes in the electroencephalo-
`graphic median frequency were followed to quan-
`tify the anesthetic effect of R( - )-ketamine and
`S( + )-ketamine in a subject who received an
`infusion of these two optical isomers on separate
`occasions. Shown is the percent reduction in the
`median frequencies versus plasma concentration.
`Although characteristic S-shaped, or sigmoidal,
`curves are seen with both compounds, they differ
`in both maximum effect achieved, E , and con-
`centration needed to produce 50% of E , the
`ECro. These relationships may be considered direct
`ones as no significant time delay was found between
`response and concentration (1 mg/L = 4.2 LIM).
`(Redrawn from Schuttler, J., Stoeckel, H., Schweil-
`den, H., and Lauvan, P.M.: Hypnotic drugs. In
`Quantitation, modeling and control in anaesthesia.
`Edited by H. Stoeckel. Stuttgart, George Thieme
`Verlag, 1985, pp. 196-210.)
`
`20
`
`ONSE
`
`response
`
`pared to
`ns for the
`
`•ween re-
`
`ivenously
`and the
`
`on of re-
`
`Ing when
`levels for
`
`sponse is
`nentially.
`
`-gimen are
`dlationship,
`d response
`with short
`le of active
`lin greater
`,onse is ex-
`elationship
`!ntration.
`
`Teen place-
`Ierlying re-
`asure con-
`;an system,
`; that arise,
`
`111
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`342
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`PHAI7 '.*.ACOtOGIC RESPONSE (cid:9)
`
`CHAPTER 20
`
`tration around the ECG value. For example, if 7 = 1 then, by appropriate substitution into
`Eq. 1, the concentrations corresponding to 20% and SO% of maximal response are 0.25
`and 4 times EC50, respectively, a 16-fold range. Whereas, if y = 2, the corresponding
`concentrations are 0.5 and 2 times EC5„, only a fourfold range. Using the percent decrease
`in heart rate during a standard exercise as a measure of response to propranolol, the average
`value of y is close to 1 (Fig. 20-3). Generally, the value of y lies between 1 and 3. Occa-
`
`Shape Factor
`5
`
`A
`
`Shape Factor
`5
`
`100
`
`08
`
`(.3')
`0.0
`61'
`ac
`'Fs 60
`E
`
`40
`
`rs 20
`n.
`
`0
`
`100
`Na)
`O 80
`ca.
`G)
`cC
`70 60
`E
`23
`-40
`45
`
`20
`
`a.
`
`0
`
`0 (cid:9)
`
`1 (cid:9)
`
`4
`
`5 (cid:9)
`
`0.1 (cid:9)
`
`3 (cid:9)
`2 (cid:9)
`Concentration/EC50 (cid:9)
`Fig. 20-2. Linear (A) and semilogarithmic (B) concentration-response plots. predicted according to Eq. 1. for
`three lopothetical drugs that have the same EC: 5,, value but different values of the shape factor, y. At low con-
`centrations the effect increases almost linearly with concentration (A). when y A 1. approaching a maximal value
`at high concentrations. The greater the value of y. the steeper is the change in response around the EC50 value.
`Between 20 and 60% of maximal effect (colored dashed lines). the response appears to be proportional to the
`logarithm of the concentration (B) for all values of y. Concentrations are expressed relative to EC,.
`
`1
`Concentration/EC50
`
`10
`
`Fig. 20-3. Response, measured by the percent
`decrease in exercise-induced tachycardia. to pro-
`pranolol increases with the unbound concentra-
`tion of the drug in plasma. The data points rep-
`resent measurements after single and multiple
`(daily) oral doses of two 60-mg tablets of pro-
`prandol (0) or a 160-mg sustained-release cap-
`sule (0) in an individual subject. The colored line
`is the fit of Eq. 1 to the data. The response ap-
`pears to follow the E„,,„ model with a y of 1, an
`of 40%, and an ECso of 5.3 pg/L (Redrawn
`from Lalonde, R.L., Straka, 11.5., Pieper, JA.,
`Bottorff. Nl.B., and Minis, D.M.: Propranolol
`phannacxxlynamie modeling using unbound and
`total concentrations in healthy volunteers. J.
`Phannaeolinet. Biopharm., 15:569482. 1997.)
`
`40
`
`co
`Co
`Cc
`.=
` 30
`
`20
`
`cw
`C.) a,
`O
`
`8 10
`a.
`
`0
`
`0 (cid:9)
`
`5 (cid:9)
`15 (cid:9)
`10 (cid:9)
`20 (cid:9)
`Unbound Concentration, lig&
`
`25
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