-.
`
`
`Handbook
`
`of
`
`Basic
`
`Pharmacokinetics
`
`. . . including Clinical Applications
`
`
`
`
`
`FOURTH EDITION
`
`
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`NOVARTIS EXHIBIT 2060
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 6
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`r
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`To my wife, Ingrid
`
`Handbook
`
`of
`
`Basic
`
`Pharmacokinetics
`
`. . . including Clinical Applications
`
`
`
`
`
`by W. A. Ritschel
`
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`Ph.D., M.D., Mr. Pharm., F.A.S.A., F.C.P.
`
`Professor of Pharmacokinetics
`
`
`
`
`
`and Biopharmaceutics
`College of Pharmacy
`
`
`
`Professor of Pharmacology
`
`
`
`
`
`-:-CIENTIF/C& TEe .. HNICAlnd Cell Biophysics
`
`
`
`
`'~NFnp~'AT(nM!;~t-lT~.Ff0I!ege of ~e~icin~
`
`
`
`' l'Tirlverslty of Cmcmnatl
`
`
`
`
`
`JUN 2 1 199 j
`
`
`
`Cincinnati 45267
`
`Y., ~;\ , _ .. ' - _ . :~~AI1I\Offe(;;_
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`
`
`
`
`FOURTH EDITION, 1992
`
`
`DnUG INTELLIGENCE PUBLICATIONS, INC.
`
`
`
`
`HAMILTON, IL 62341
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`
`
`
`
`•
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`NOVARTIS EXHIBIT 2060
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 6
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`

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`Copyright © 1992 by
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`DRUG INTELLIGENCE PUBLICATIONS, INC.
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`
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`
`1241 Broadway, Hamilton, IL 62341 U.S.A.
`
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`All rights, including that of translation, reserved . T his book is protected
`by copyright. No part of this book may bc rcproduced in any form or by
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`any means, including photocopying, or utilized by any information
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`storage and retrieval system without prior written permission from the
`copyright owner.
`
`
`
`Library of Congress Cataloging-in-Publication Data
`
`
`
`
`
`
`mtschel, W. A. (Wolfgang A.)
`
`
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`Handbook of basic pharmacokinetics-including
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`
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`clinical applications/by W. A. Ritschel - 4th cd.
`
`
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`
`
`
`588 p. 10.8 X 18.2 em.
`
`
`
`
`
`
`Includes bibliographical references and index.
`
`
`
`ISBN 0-914768-50-6 (soft)
`I. Title.
`I. Pharmacokinetics-Handbooks, manuals, etc.
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`[DNLM: 1. Biopharmaceutics. 2. Chemistry, Pharmaceutical.
`
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`3. Drug Interaclions. 4. Kinetics. 5. Pharmacology.
`QV 38 R612h]
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`RM301.5.R57
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`615'.7- dc20
`DNLMIDLC
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`
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`for Library of Congress
`
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`1992
`
`
`91-38402
`
`CIP
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`I(
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`NOTICE
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`The information in this book has been derived from a wide variety of
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`published drug information as well as appropriate unpublished data.
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`While diligent care has been taken to assure the accuracy of the book's
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`
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`content when it went to press, neither the author nor the publisher can
`be responsible [or the continued accuracy and completeness of informa(cid:173)
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`tion or any consequences therefrom. Ongoing research and new
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`developments in the field should be consulted.
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`Pri nuxl ill the United States of America by Production Press, Inc.
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`Jacksonville, Il linois 62650
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`Fourth Edition 1992
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`
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`First Printing 1992
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`Second Printing 1995
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`NOVARTIS EXHIBIT 2060
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`Page 3 of 6
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`6
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`Dose Dumping is a term used to describe the
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`achievement of sustained drug concentration by
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`simply increasing the dose size or by accidental
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`fast release of drug from a sustained release dosage
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`form.
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`Dose-Response Curve is the graphical presenta(cid:173)
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`tion of the pharmacological or clinical effectiveness
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`or toxicity (response) versus dose. A log dose-re(cid:173)
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`sponse curve is sigmoid with a straight-line ~iddle
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`section; a log dose-probability curve results III an
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`entirely straight line.
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`Dose Size is the amount of drug in lAg ( = mcg) ,
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`mg, units or other dimensions to be administered.
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`Dosing Interval is the time period between ad(cid:173)
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`ministration of maintenance doses.
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`A Drug is a chemical compound of synthetic,
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`semisynthetic, natural or biological origi,? whic~ in(cid:173)
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`teracts with human or animal cells. The mterachons
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`may be quantified, whereby these resulting actions
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`are intended to prevent, to cure or to reduce ill
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`effects in the human or animal body, or to detect
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`disease-causing manifestations.
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`A Drug Specialty or Brand Product is a drug
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`product, usually of unvarying com~osition, labeled
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`with a registered trade mark of a smgle company.
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`Drug Release or Liberation is the delivery of the
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`active ingredient from a dosage form .into .solutio?
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`The dissolution medium is either a bIOlogICal flUId
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`or an artificial test fluid (in vitro). Drug release is
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`characterized by the speed. (liberation rate con-
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`7
`DEFINITIONS AND GLOSSARY
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`stant) and the amount of drug appearing in solu(cid:173)
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`tion.
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`A Drug Product or Dosage Form is the gross
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`pharmaceutical form containing the active in(cid:173)
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`[drug(s)] and vehicle substances
`gredient(s)
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`necessary in formulating a medicament of desired
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`dosage, desired volume and desired application
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`form, ready for administration.
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`Drug-Receptor Interaction is the combining of a
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`drug molecule with the receptor for which it has
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`affinity, and the initiation of a pharmacologic
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`response by its intrinsic activity.
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`Elimination Half-Life of a drug is the time in
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`hours necessary to reduce the drug concentration
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`in the blood, plasma or serum to one-half after
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`equilibrium is reached. The elimination half-life
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`may be influenced by: dose size, variation in
`urinary excretion (pH),
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`intersubject variation,
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`age, protein binding, other drugs and diseases
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`(especially renal and liver diseases).
`Loss of drug from the body, as described by the
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`elimination half-life, means the elimination of the
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`administered parent drug molecule
`(not
`its
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`metabolites) by urinary excretion, metabolism or
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`other pathways of elimination (lung, skin, etc.).
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`Enterohepatic Recirculation (Biliary Recycling)
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`is the phenomenon in which drugs emptied via bile
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`into the small intestine can be reabsorbed from the
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`intestinal lumen into systemic circulation.
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`Enzyme Induction is the increase in enzyme
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`content or rate of enzymatic processes resulting in
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`NOVARTIS EXHIBIT 2060
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`Page 4 of 6
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`

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`264
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`Equation 17 Al can be rewritten for total drug
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`concentration:
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`Eq. 17.49
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`and, hence, the free drug concentration is:
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`css, f = DIT
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`u
`-
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`Clintr
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`-
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`Eq.17.50
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`The influence of protein binding due to dis(cid:173)
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`placement from binding on pharmacokinetic
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`parameters is shown in Table 17-14.
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`Inspection of Tables 17-3 and 17-4 reveals some
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`important facts which can be summarized as
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`follows:
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`• Change in liver blood flow will influence the
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`rate of metabolism of drugs with high extrac(cid:173)
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`tion ratios (E > 0.7). Increase in liver blood
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`flow will increase hepatic and total clear(cid:173)
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`ance.
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`• Change in liver blood flow will not influence
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`drugs with low extraction ratios (E < 0.3).
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`• Change in protein binding of drugs with high
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`extraction ratios (E > 0.7) will not influence
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`total clearance.
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`• Decrease in protein binding increases the
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`total clearance of drugs with low extraction
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`ratios (E < 0.3).
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`• Decrease in protein binding does not in(cid:173)
`fluence the total clearance of drugs with high
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`extraction ratios (E > 0.7). However, be-
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`265
`CLEARANCE
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`cause the intrinsic clearance decreases, the
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`free drug concentration increases; hence,
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`pharmacodynamic response may increase.
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`• In the relationship between Cltot. V d and tl/2'
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`total clearance and volume of distribution
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`are the independent variables, the elimina(cid:173)
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`tion half-life is the dependent variable:
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`0.693, Vd
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`tl/2 = _ _ _ _
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`Cltot
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`Eq.17 .51
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`For clinical applications, it is not feasible to col(cid:173)
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`lect a sufficient number of blood samples to either
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`perform pharmacokinetic parameter calculations
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`after curve-fitting, or to calculate the AUC. Two
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`methods can be used for estimating the total
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`clearance from a single blood sample. If the
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`bioavailability is not known, the clearance is
`Cltot/f:
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`Method I
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`Method I is based on a blood sample C(t) taken
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`during the terminal phase, the literature value for
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`Vd, and the body weight, BW:
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`D
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`Cltot/f = [In (_
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`) -
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`Vd/f
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`Vd/f
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`In C(t)]. _
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`t
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`. BW
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`Eq.17.52
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`Method II
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`Method II is based on the postulate that in the
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`absence of enzyme induction or enzyme inhibi(cid:173)
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`tion, the total area under the curve after a single
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`dose, AUCo-oo, is equal to the area under the
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`curve during one dosing interval at steady state,
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`NOVARTIS EXHIBIT 2060
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`Page 5 of 6
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`266
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`AUCTn-Tn+l. AUCTn-+Tn+l can be obtained frOth
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`the steady state concentration:
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`<,\
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`Eq. 17.53
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`Eq. 17.54
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`or
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`D
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`Cltotlf = -~,----
`C~v • T
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`Eq.17.55
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`If one wants to convert the total plasma
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`clearance to blood clearance, Equation 17.56 can
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`be used:
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`Cltot blood
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`Cltot plasma
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`I-Hematocrit
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`Eq. 17.56
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`~or drugs bound to erythrocytes, Equation 17.57
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`IS used:
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`Cltot blood
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`Cltot plasma
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`Eq. 17.57
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`
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`where A
`is
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`blood/plasma.
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`the drug concentration
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`ratio
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`267
`CLEARANCE
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`Table 17-13. Influence of Change in Blood Flow on
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`Total Clearance and Extraction Ratio
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`CHANGE IN:
`DR~~ERTY:
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`
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`Extraction Ratio Total Clearance
`BLOOD
`E
`FLOW
`PXR TRACTION RATIO E
`Cltol
`
`
`
`
`
`
`:----~------------------~--
`
`
`LOW
`n.C .
`
`E < 0.3
`
`
`
`n.c .
`
`
`n.C.
`High
`
`~=.~7 ____ ____ __ _ n._c_. _______ _
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`t" Increase; ~ = decrease; n.c. = no change
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`Table 17-14. Influence of Change in Protein Binding due to
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`Displacement (Increase in Free, Unbound Fraction iu) from
`
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`Protein Binding On Apparent Volume of Distribution, Vd,
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`
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`Elimination Half-Life, tl/2, Total Clearance, Cltoto Intrinsic
`
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`
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`Clearance, Clintro Total Area Under the Curve, AUCo-+oo,
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`
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`~ Pharmacologic Response, R.
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`DRUG PROPERTY: ____ C_H_A_N_G_ E _IN_: ________ __
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`
`
`
`EXTRACTION
`
`
`RATIO E
`LoW
`
`
`E < 0.3
`
`
`
`Vd
`Large
`
`Small
`
`
`
`Vd
`t
`n.c.
`
`
`
`t'l'
`
`Cllot
`
`
`
`
`
`
`Cllntr AUCo~oo R
`
`n.C.
`
`n.c.
`
`
`Large
`
`n.c.
`High
`
`
`E > 0.7
`
`n.C.
`Small
`
`
`n.c.
`
`
`t = increase; ~ '" decrease; n.c. = no change
`
`
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`
`
`n.c.
`
`n.c.
`
`
`Extrarenal Clearance Clext l"lIren.
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`
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`Being able to calculate the total clearance from
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`blood level curves and the renal clearance from
`
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`blood and urine data, it is then possible to combine
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`all other pathways of excretion, including metabo(cid:173)
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`lism, in one parameter, the extrarenal clearance
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`which is the difference between the total and the
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`
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`renal clearance as given in Equation 17.58.
`
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`Clextrnren. = Cl tot -- Clren . corr. [ml/min]
`
`
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`
`
`Eq. 17.58
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`NOVARTIS EXHIBIT 2060
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`Page 6 of 6
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