`Clinical Pharmacokinetics
`
`MILO GIBALDI, PH.D.
`Dean, School of Pharmacy
`Associate Vice President,
`Health Sciences
`University of Washington
`Seattle, Washington
`
`E.S. FARLEY LIBRARY
`WILKES UNIVERSITY
`WILKES-BARRE, PA
`
`FOURTH EDITION
`
`LEA & FEBIGER
`
`• Philadelphia
`
`• London
`
`•
`
`1991
`
`Page 1
`
`SHIRE EX. 2049
`KVK v. SHIRE
`IPR2018-00290
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`Lea & Febiger
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`Library of Congress Cataloging-in-Publication Data
`
`Gibaldi, Milo.
`Biopharmaceutics and clinical pharmacokinetics / Milo Gibaldi.-
`4th ed.
`P.
`cm.
`Includes bibliographical references.
`ISBN 0-8121-1346-2
`1. Biopharmaceutics. 2. Pharmacokinetics. I. Title
`[DNLM: 1. Biopharmaceutics. 2. Pharmacokinetics. QV 38 G4371)]
`RM301.4.G53 1990
`615' .7—dc20
`DNLM/DLC
`for Library of Congress
`
`90-5614
`CIP
`
`First Edition, 1971
`Reprinted 1973, 1974, 1975
`Second Edition, 1977
`Reprinted 1978, 1979, 1982
`Third Edition, 1984
`Reprinted 1988
`Fourth Edition, 1991
`First Spanish Edition, 1974
`First Japanese Edition, 1976
`Second Japanese Edition, 1981
`Second Turkish Edition, 1981
`
`The use of portions of the text of USP XX-NF XV is by permission of the USP Convention. The Convention
`is not responsible for any inaccuracy of quotation or for false or misleading implication that may arise
`from separation of excerpts from the original context or by obsolescence resulting from publication of a
`supplement.
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`Reprints of chapters may be purchased from Lea & Febiger in quantities of 100 or more.
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`Copyright © 1991 by Lea & Febiger. Copyright under the International Copyright Union. All Rights Reserved. This
`book is protected by copyright. No part of it may be reproduced in any manner or by any means without written permission
`from the publisher.
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`PRINTED IN THE UNITED STATES OF AMERICA
`
`Print no.: 4 3 2 1
`
`Page 2
`
`
`
`
`
`APPENDIX II
`
`Method of Superposition
`
`The method of superposition is a useful non-
`compartmental approach for predicting drug ac-
`cumulation and steady-state concentrations on re-
`petitive dosing from data obtained after a single
`dose. The theoretical basis for superposition is
`merely that drug concentration is proportional to
`dose.
`The application of superposition to predict the
`time course of drug concentration under different
`conditions requires several assumptions. The first
`is that, irrespective of time of administration, a
`given single dose administered by a given route
`will always give rise to the same drug concentra-
`tion-time curve. A change in dose, but not in route
`of administration, is reflected by a proportional
`change in drug concentration at any time after ad-
`ministration. During repetitive administration,
`blood levels arising from a given dose are simply
`an additive function of the blood levels associated
`with that dose and the blood levels resulting from
`previous doses. This principle is illustrated in Table
`II-1.
`Table II-1 shows how the method of superpo-
`sition can be used to predict drug concentrations
`
`during multiple dosing. In this particular example,
`drug concentration-time data was obtained after a
`single dose (see column 2). We wish to predict
`drug concentrations on repetitive administration of
`the same dose given every 3 hr. Each subsequent
`dose, if given independently, would give rise to
`the same concentrations as the first dose; this is
`indicated by the values in parentheses. The net
`concentration after the second, third, or subsequent
`doses, however, must also reflect the contribution
`of previous doses.
`If given independently, the second dose would
`provide a drug concentration of 7µg/ml 1 hr after
`administration. When given after the first dose,
`however, the second dose gives rise to a drug con-
`centration of 9.5 µg/ml 1 hr after dosing; 2.5 vt-g/
`ml of drug concentration is contributed by the first
`dose. One hr after giving the third dose, drug con-
`centration equals 9.7 µ,g/m1 (rather than 7 µg/ml)
`because of the contributions from the two previous
`doses.
`The data in Table I-1 also indicate that steady
`state is achieved after the third dose, because drug
`concentrations following the third, fourth, and sub-
`sequent doses are identical.
`
`Table II-1. Drug Concentrations (µ,g/m1) During 4 Consecutive Doses Given at 3-hr Intervals
`(See Text for Detailed Explanation)
`First
`dose
`
`Time
`
`Second
`dose
`
`Third
`dose
`
`Fourth
`dose
`
`0
`7
`10
`5
`2.5
`1.25
`0.6
`0.2
`0
`
`0
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`
`(+0)
`(+7)
`(+10)
`(+5)
`(+2.5)
`(+1.25)
`(+0.6)
`(+0.2)
`(+0)
`
`5
`9.5
`11.25
`5.6
`2.7
`1.25
`0.6
`0.2
`0
`
`(+0)
`(+7)
`(+10)
`(+5)
`(+2.5)
`(+1.25)
`(+0.6)
`
`5.6
`9.7
`11.25
`5.6
`2.7
`1.25
`0.6
`
`(+0)
`(+7)
`(+ 10)
`(+5)
`
`5.6
`9.7
`11.25
`5.6
`
`379
`
`Page 3
`
`