`
`Handbook
`of
`Basic
`Pharmacokinetics
`
`. . . including Clinical Applications
`
`FOURTH EDITION
`
`NOVARTIS EXHIBIT 2017
`Par v. Novartis, IPR 2016-01479
`Page 1 of 6
`
`
`
`To my wife, Ingrid
`
`'
`
`Handbook
`of
`Basic
`Pharmacokinetics
`... including Clinical Applications
`
`by W. A. Ritschel
`Ph.D., M.D., Mr. Pharm., F.A.S.A., F.C.P.
`
`Professor of Pharmacokinetics
`and Biopharmaceutics
`College of Pharmacy
`Professor of Pharmacology
`t"CIENTiFIC& TEC. HNICAt,nd Cell Biophysics
`· ;NFfiP~ ~l!TlON ~J:MT~.Ffol!ege of ~e?icin~
`· l'Jirlvers1ty of Cmcmnati
`JUN 2 1 199 J
`Cincinnati 45267
`
`i~
`' '• ·•
`
`-;,.;~ : •• _ .:..1..::~-:AiiKOffi(;:._
`FOURTH EDITION, 1992
`DIIUG INTELLIGENCE PUBLICATIONS, INC.
`HAMILTON, IL 62341
`
`'
`
`NOVARTIS EXHIBIT 2017
`Par v. Novartis, IPR 2016-01479
`Page 2 of 6
`
`
`
`Copyright © 1992 by
`DRUG INTELLIGENCE PUBLICATIONS, INC.
`1241 Broadway, Hamilton, IL 62341 U.S.A.
`
`All rights, including that of translation, 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 prior written permission from the
`copyright owner.
`
`Library of Congress Cataloging-in-Publication Data
`
`Ritschel, W. A. (Wolfgang A.)
`including
`Handbook of basic pharmacokinetics-
`clinical applications/by W. A. Ritschel - 4th ed.
`
`588 p. 10.8 X 18.2 cm.
`Includes bibliographical references and index.
`ISBN 0-914768-50-6 (soft)
`I. Title.
`l. Pharmacokinetics-Handbooks, manuals, etc.
`[DNLM: l. Biopharmaceutics. 2. Chemistry, Pharmaceutical.
`3. Drug Interactions. 4. Kinetics. 5. Pharmacology.
`QV 38 R612h]
`RM301.5.R57
`615'.7-dc20
`DNLM/DLC
`for Library of Congress
`
`1992
`
`91-38402
`CIP
`
`[
`
`NOTICE
`
`The information in this book has been derived from a wide variety of
`published drug information as well as appropriate unpublished data.
`While diligent care has been taken to assure the accuracy of the book's
`content when it went to press, neither the author nor the publisher can
`be responsible for the continued accuracy and completeness of informa(cid:173)
`tion or any consequences therefrom. Ongoing research and new
`developments in the field should be consulted.
`
`Printed in the United States of America by Production Press, Inc.
`Jacksonville, Illinois 62650
`
`Fourth Edition 1992
`First Printing 1992
`Second Printing 1995
`
`NOVARTIS EXHIBIT 2017
`Par v. Novartis, IPR 2016-01479
`Page 3 of 6
`
`
`
`r
`
`6
`
`Dose Dumping is a term used to describe the
`achievement of sustained drug concentration by
`simply increasing the dose size or by accidental
`fast release of drug from a sustained release dosage
`form.
`
`Dose-Response Curve is the graphical presenta(cid:173)
`tion of the pharmacological or clinical effectiveness
`or toxicity (response) versus dose. A log dose-re(cid:173)
`sponse curve is sigmoid with a straight-line ~iddle
`section; a log dose-probability curve results m an
`entirely straight line.
`
`Dose Size is the amount of drug in µg ( = mcg),
`mg, units or other dimensions to be administered.
`
`Dosing Interval is the time period between ad(cid:173)
`ministration of maintenance doses.
`
`A Drug is a chemical compound of synthetic,
`semisynthetic, natural or biological origin which in(cid:173)
`teracts with human or animal cells. The interactions
`may be quantified, whereby these resulting actions
`are intended to prevent, to cure or to reduce ill
`effects in the human or animal body, or to detect
`disease-causing manifestations.
`
`A Drug Specialty or Brand Product is a drug
`product, usually of unvarying composition, labeled
`with a registered trade mark of a single company.
`
`Drug Release or Liberation is the delivery of the
`active ingredient from a dosage form into solution.
`The dissolution medium is either a biological fluid
`or an artificial test fluid ( in vitro). Drug release is
`characterized by the speed. ( liberation rate con-
`
`7
`DEFINITIONS AND GLOSSARY
`stant) and the amount of drug appearing in solu(cid:173)
`tion.
`
`A Drug Product or Dosage Form is the gross
`pharmaceutical form containing the active in(cid:173)
`gredient(s)
`[ drug(s)] and vehicle substances
`necessary in formulating a medicament of desired
`dosage, desired volume and desired application
`form, ready for administration.
`
`Drug-Receptor Interaction is the combining of a
`drug molecule with the receptor for which it has
`affinity, and the initiation of a pharmacologic
`response by its intrinsic activity.
`
`Elimination Half-Life of a drug is the time in
`hours necessary to reduce the drug concentration
`in the blood, plasma or serum to one-half after
`equilibrium is reached. The elimination half-life
`may be influenced by: dose size, variation in
`urinary excretion (pH),
`intersubject variation,
`age, protein binding, other drugs and diseases
`( especially renal and liver diseases).
`Loss of drug from the body, as described by the
`elimination half-life, means the elimination of the
`(not
`its
`administered parent drug molecule
`metabolites) by urinary excretion, metabolism or
`other pathways of elimination (lung, skin, etc.).
`
`Enterohepatic Recirculation (Biliary Recycling)
`is the phenomenon in which drugs emptied via bile
`into the small intestine can be reabsorbed from the
`intestinal lumen into systemic circulation.
`
`Enzyme Induction is the increase in enzyme
`content or rate of enzymatic processes resulting in
`
`NOVARTIS EXHIBIT 2017
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`
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`264
`Equation 17.41 can be rewritten for total drug
`concentration:
`
`DIT
`css = - - -
`
`Eq. 17,49
`
`and, hence, the free drug concentration is:
`css • f = DIT
`u - -
`Clintr
`
`Eq. 17.50
`
`The influence of protein binding due to dis(cid:173)
`placement from binding on pharmacokinetic
`parameters is shown in Table 17-14.
`Inspection of Tables 17-3 and 17-4 reveals some
`important facts which can be summarized as
`follows:
`• Change in liver blood flow will influence the
`rate of metabolism of drugs with high extrac(cid:173)
`tion ratios (E > 0. 7). Increase in liver blood
`flow will increase hepatic and total clear(cid:173)
`ance.
`
`• Change in liver blood flow will not influence
`drugs with low extraction ratios (E < 0.3).
`• Change in protein binding of drugs with high
`extraction ratios (E > 0. 7) will not influence
`total clearance.
`
`• Decrease in protein binding increases the
`total clearance of drugs with low extraction
`ratios (E < 0.3).
`• Decrease in protein binding does not in(cid:173)
`fluence the total clearance of drugs with high
`extraction ratios (E > 0. 7). However, be-
`
`265
`CLEARANCE
`cause the intrinsic clearance decreases, the
`free drug concentration increases; hence,
`pharmacodynamic response may increase.
`• In the relationship between Cltot, V d and t112,
`total clearance and volume of distribution
`are the independent variables, the elimina(cid:173)
`tion half-life is the dependent variable:
`o.693. vd
`t112 = - - - (cid:173)
`Cltot
`
`Eq. 17.51
`
`For clinical applications, it is not feasible to col(cid:173)
`lect a sufficient number of blood samples to either
`perform pharmacokinetic parameter calculations
`after curve-fitting, or to calculate the AUC. Two
`methods can be used for estimating the total
`clearance from a single blood sample. If the
`bioavailability is not known, the clearance is
`Cltotf f:
`
`Method I
`Method I is based on a blood sample C(t) taken
`during the terminal phase, the literature value for
`V d, and the body weight, BW:
`
`D
`Cltotlf = [In(_
`) -
`Vd/f
`
`Vd/f
`In C(t)] • _
`. BW
`
`t
`
`Eq. 17.52
`
`Method II
`Method II is based on the postulate that in the
`absence of enzyme induction or enzyme inhibi(cid:173)
`tion, the total area under the curve after a single
`dose, AUC 0 -oo, is equal to the area under the
`curve during one dosing interval at steady state,
`
`NOVARTIS EXHIBIT 2017
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`266
`AUCTn .... Tn+1, AUCTn .... Tn+1 can be obtained froth
`the steady state concentration:
`·•1
`
`Table 17-13. Influence of Change in Blood Flow on
`Total Clearance and Extraction Ratio
`
`CLEARANCE
`
`267
`
`Eq. 17,53
`
`oRUG oPERTY:
`~~TRACTION RATIO E
`
`BLOOD
`FLOW
`
`LOW
`E < 0.3
`
`CHANGE IN:
`Extraction Ratio Total Clearance
`E
`Cltot
`n.c.
`n.c.
`
`Eq. 17.54
`
`or
`
`D
`Cltotlf = --cc~--
`C~v • T
`
`Eq. 17.55
`
`If one wants to convert the total plasma
`clearance to blood clearance, Equation 17.56 can
`be used:
`
`n. c.
`High
`E > 0.7
`n.c.
`1 = Increase; • = decrease; n.c. = no change
`Table 17-14. Influence of Change in Protein Binding due to
`Displacement (Increase in Free, Unbound Fraction fu) from
`protein Binding On Apparent Volume of Distribution, Vd,
`Elimination Half-Life, t112, Total Clearance, Cltot, Intrinsic
`Clearance, Clintr, Total Area Under the Curve, AUC 0 -+ 00 ,
`and Pharmacologic Response, R.
`
`DRUG PROPERTY: ____ C_H_A_N_G_ E_ IN_: ________ _
`EXTRACTION
`RATIO E
`
`vd
`large
`Small
`
`vd
`t
`n.c.
`
`t,,,
`
`Cltot
`
`Clint, AUCo-oo R
`n.c.
`?
`n.c.
`?
`
`Cltot blood
`
`Cltot plasma
`
`1-Hematocrit
`
`Eq. 17.56
`
`LOW
`E < 0.3
`
`~or drugs bound to erythrocytes, Equation 17.57
`1s used:
`
`large
`n.c.
`High
`E > 0.7
`Small
`n.c.
`n.c.
`t = increase; • = decrease; n.c. = no change
`
`n.c.
`n.c.
`
`Cltot blood
`
`Cltot plasma
`
`Eq. 17.57
`
`Extrarenal Clearance Clextrnren.
`
`where A
`is
`blood/plasma.
`
`the drug concentration
`
`ratio
`
`Being able to calculate the total clearance from
`blood level curves and the renal clearance from
`blood and urine data, it is then possible to combine
`all other pathways of excretion, including metabo(cid:173)
`lism, in one parameter, the extrarenal clearance
`which is the difference between the total and the
`renal clearance as given in Equation 17.58.
`
`Clextrnren. = Cltot - Clren. corr. [ml/min]
`
`Eq. 17.58
`
`NOVARTIS EXHIBIT 2017
`Par v. Novartis, IPR 2016-01479
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