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`Sawai (IPR2019-00789), Ex. 1047, p. 001
`
`

`

`tñ,nætuIitlt@
`
`:ì,
`
`Applied Biopharmaceutics and Fharmacokinetics' Fifth Edition
`
`Copyright@2005byTheMcGraw-HillCompanies'Inc'Copyright@1999'1993byAppleton
`& Lange; copyright O 1985, 1980 by Appléton-Century-Ciofts' All rights reserved' Printed
`intheUnitedStatesofAmerica.ExceptaspermittedundertheUnitedStatescopyright
`Act of 1976, no part of this publication muy-be reproduced or-distributed in any form or
`by any means, or stored i., å daa base or retrieval system, without the prior written per-
`mission of the Publisher.
`7890 DOC/DOC 0
`
`rsBN 0-07-137550-3
`
`This book was set in New Baskerville by TechBooks'
`The editors were Michael Brown and Christie Naglieri
`The production service was TechBooks'
`The production supervisor was Phil Galea'
`The cover designer was KellY Parr'
`RR Donnelley was Printer and binder'
`
`This book is printed on acid-free paper'
`
`I-ibrary of Congress Cataloging-in-Fublication Data
`Shargel, Leon, 1941-
`Ápplied biopharmaceutics & pharmacokinetics/Leon shargel, susanna wu-Pong,
`Andrew B.C. Yu. -5th ed.
`P' ;cm'
`Includes bibliographical references and index'
`ISBN 0-07-137550-3
`l.Biopharmaceutics.2.Pharmacokinetics.I.Title:Appliedbiopharmaceuticsand
`pharmacokinetics' II. Wu-Pong, Susanna' III' Yu' Andrew B' C''
`1945- IV. Title.
`IDNLM:l.Biopharmaceutics.2'Models,Chemical'3'Pharmacokinetics.
`QV 38 S531a 20041 RM301 .4.552 2004
`675',7-dc22
`
`2004044993
`
`Flease tell the authors and publisher what you think of this book by sending yoür
`corr¡rnents to pharmacy@någraw-hill.com. please put the author and title of the
`book in the subject line.
`
`Sawai (IPR2019-00789), Ex. 1047, p. 002
`
`

`

`,.åi{
`
`re
`
`'Appleton
`d. Printed
`copyright
`ry form or
`ritten per-
`
`Wu-Pong,
`
`:eutics and
`
`[rcs
`
`2004044993
`
`:nding your
`title of the
`
`CONTTENTS
`
`Prefuce / XV
`Glossary/XWI
`
`1.. INTRODUCTION TO BIOPHARMACEUTICS AND
`PHARIvTACOKINETICS/1
`Biopharmaceutics/ 1
`Pharmacokir'etics/3
`Clinical Pharmacokinetics/3
`Pharmcodynamics/ 4
`Toxicokinetics and Clinical Toxicology/4
`Measurement of Drug Concentrations/5
`Basic Pharmacokinetics and Pharmacokinetic Models/9
`References,/18
`Bibliography/18
`
`2. MATHEMATIC FUNDAMENTALS IN
`PHARtvtACO KI N ETICS/21
`Math SelÊExarn/2\
`Estimation and the Use of Calculators and Computers/Z2
`Calc:r:Jus/27
`Graphs/30
`Units in Pharmacokinetics / 37
`Measurement and Use of Significant Figures/38
`Units for Expressing Blood Concentrations/39
`Statistics/39
`Rates and Orders of Reactions/42
`Frequently Asked Questions/47
`Learning Questions/48
`References/50
`Bibliography/50
`
`V
`
`Sawai (IPR2019-00789), Ex. 1047, p. 003
`
`

`

`-
`
`VI
`
`coNTENTS
`
`3. ONE-COMPARTMENT OPEN MODEL: TNTRAVENOUS
`BOLUS ADMI N ISTRATION/s1
`Elimination Rate Constant,/52
`Apparent Volume of Distribution/ 53
`Clearance/57
`Calculation of Kfrom Urinary Excretion Data/63
`Frequentþ Asked Questions/ 69
`Learning Questions/69
`Fieference/72
`Bibliography/72
`
`4. MULTICOMPARTMENTAL MODELS: INTRAVENOUS
`BOLUS ADMIN I STRATION/73
`Two-Compartment Open Model/75
`Three-Compartment Open Model/93
`Determination of Compartment Models/95
`Frequentþ Asked Questions/ 101
`Learning Questions/ 102
`References/105
`Bibliography/105
`
`5. INTRAVENOUS INFUSION/1OS
`One-Compartment Model Drugs/108
`Infusion Method for calculating Parient Elimination H:alf-Life/112
`Loading Dose Plus fV Infusion: One-Compartment Model/115
`Estimation of Drug Clearance and Vp from InfusionData/122
`Intravenous Infusion of Two Compartment Model Dtugs/122
`Loading Dose Plus fV Infusion: Two-Compartment Model/I23
`Frequently Asked Questions/ 127
`Learning Questions/ I 27
`Reference/129
`Bibliography/129
`
`6, DRUG ELIMINATION /ffi]D CLEARANCE/131
`Drug Elimination/ 73I
`The Kidney/132
`
`Sawai (IPR2019-00789), Ex. 1047, p. 004
`
`

`

`CONTENTS VTI
`
`Renal Drug Excretion/ 136
`Drug Clearance/L39
`Clearance Models/142
`Renal Clearance/144
`Determination of Renal Clearance / I 49
`Relationship of clearance to Elimination HalÊLife and volume of
`Distribution/155
`Frequently Asked Questions/ 1 57
`Learning Questions/ 1 58
`References/159
`Bibliography/ 159
`
`7. PHARMACOKINETICS OF ORAL ABSORPTION/161
`Pharmacokinetics of Drug Absorption/161
`Zero-Order Absorption Model/ 163
`First-Order Absorption Model/ 164
`Significance of Absorption Rate Constants/ 1 81
`Frequentþ Asked Questions/ 1 82
`Learning Questions/ 1 82
`References/184
`Bibliography/ 184
`
`8. MULTIPLE DOSAGE RTGIMEN5/185
`Drug Accumlation/185
`Repetitive Intravenous Injections/ 190
`Intermittent Intravenous Infusion/ 197
`Estimation of h and Vp of Aminoglycosides in Clinical Situations/2Ql
`Multiple-Oral-Dose Regimen/202
`Loading Dose/205
`Determination of Bioavailabiliry and Bioequivalance in a Multiple-Dose
`Regimen/207
`Bioequivalence Studies/ 208
`Dosage Regimen Schedules/2 I 0
`Frequently Asked Questions/ 2 1 5
`Learning Questions/2 1 5
`References/216
`Bibliography/21.7
`
`2
`
`Sawai (IPR2019-00789), Ex. 1047, p. 005
`
`

`

`-
`
`VIII
`
`CONTENTS
`
`9. NON LIN ËAR PHAR]VIACOKIN ETTCS/219
`Saturable Enzymatic Elimination Processes,/22 1
`Drug Elimination by Capacity-Limited Pharmacokinetics: One-Compartment
`Model, Intravenous Bolus Injection / 224
`Equations for Drugs Distributed as One-Compartment Model and
`Eliminated by Nonlinear Pharmacokinetics/239
`Bioavailability of Drugs That Follow Nonlinear Pharmacoki netics / 243
`Nonlinear Pharmacokinetics Due to Drug-Protein Binding/243
`Frequently Asked Questions/ 246
`Learning Questions/246
`References,/248
`Bibliography/248
`
`10. PHYSIOLOGIC DRUG DISTRIBUTION AND
`PROTEIN BINDING/251
`Physiologic Factors of Distributi on / 251
`Apparent Volume Distribution/ 259
`Protein Binding of Drugs/267
`Relationship of Plasma Drug-Protein Binding to Distribution and
`Elimination/275
`Determinants of Protein Binding / 27 9
`Kinetics of Protein Binding/280
`Determination of Binding Constants and Binding Sites by Graphic
`Methods/282
`Clinical Significance of Drug-Protein Binding/286
`Modeling Drug Distribution / 296
`Frequentþ Asked Questions/ 297
`Learning Questions/298
`References/299
`Bibliography/301
`
`11,. HEPATIC ELIMINATION OF DRUGS/303
`Route of Drug Administration and Extrahepatic Metabolism,/303
`Enar'me Kinetics/308
`*rn
`Anatomy and Physiology of the Liver/376
`Hepatic Enar'mes Involved in the Biotransformation of Drugs/319
`
`Sawai (IPR2019-00789), Ex. 1047, p. 006
`
`

`

`CONTENTS IX
`
`Pathways of Drug Biotransform arioú 32I
`First-Pass Effe cts / 332
`HepaticClearanceofaProtein-BoundDrug:RestrictiveandNonrestrictive
`Clearance from Bindin g/ 340
`Biliary Excretion of Drugs/344
`Frequently Asked Questions/ 348
`Learning Questions/348
`References,/351
`Bibliography/353
`
`12. PHARMACOGENETICS/355
`Example of PolYmorPhisms/ 356
`Pharmacogenomics/359
`AdverseDrugReactionsAttributedtoGeneticDifferences/361
`Genetic Polyrnorphism in Drug Metabolism: Cytochrome P-450
`Isozymes/361
`GeneticPolyrnorphisminDrugTransport:P-GlycoproteinandMultidrug
`Resistance/364
`Genetic Polymorphism in Drug Targets/365
`Pharmacokinetics/Pharmacodyrramics(PK,zPD)Considerationsand
`(PGtlPGx) / 366
`Pharmacogenetics/Pharmacogenomics
`Frequentþ Asked Questions/367
`References,/368
`BibliograPhY/369
`
`13. PHYSIOLOGIC FACTORS RELATED TO
`DRUG ABSORPTION/371
`Route of Drug Administtatiort/37I
`Nature of Cell Membranesr/373
`Passage of Drugs Across Cell Membranes/375
`Oral Drug AsorPtion/382
`Methods for Studying Factors That Affect Drug Absorption/396
`Effect of Disease States on Drug Absorptd,on/401
`Frequentþ Asked Questio ns / 405
`Learning Questions/405
`References,/406
`Bibliography/408
`
`)artment
`
`i43
`
`9
`
`Sawai (IPR2019-00789), Ex. 1047, p. 007
`
`

`

`X
`
`CoNTENTS
`
`14. BIOPHARMACEUTIC CONSIDERATIONS IN
`DRUG PRODUCT DESIGN/411
`Rate-Limiting Steps in Drug Absorption,/413
`Pharmaceutic Fac tors Affe ctin g D rug Bioava llabllity / 41 3
`Physicochemical Nature of the Drug/415
`Formulation Factors Affecting Drug Dissolu tion / 4lB
`Dissolution and Drug Release Testíng/ 42I
`Compendial Methods of Dissolution/ 424
`Meeting Dissolution Requirements / 428
`Alternative Methods of Dissolution Testing/429
`Problems of Variable Control in Dissolution Testing/430
`In-Vitro-In-Vizo Correlatio n / 437
`Biopharmaceutic Consid erations / 436
`Pharmacodynamic Consideratio ns / 437
`Drug Consid erations / 437
`Drug Product Considerations / 438
`Patient Consideratio ns / 439
`Route of Drug Administration/ 439
`Frequently Asked Questions/449
`Learning Questions/450
`References/450
`Bibliography/451
`
`1s. BIOAVAILABTLTTY AND BIOEQilVALENCE/4s3
`Definitions/453
`Purpose of Bioavailability Studies/456
`Relative and Absolute Avarlablliry / 457
`Methods for Assessing Bioavailabiliry/ 460
`Bioequivalence Studies/465
`Design and Evaluation of Bioequivalence Studies/467
`Study Designs/470
`Evaluation of t]¡le Data/ 473
`Bioe quivalen ce Example / 47 5
`Study Submission and Drug Review Process/478
`The Biopharmaceutics Classification System (BCS)/482
`Generic Biologics/485
`Clinical Significance of Bioequivalence Studies/486
`Special Concerns in Bioavailability and Bioequivalence Studies/487
`
`Sawai (IPR2019-00789), Ex. 1047, p. 008
`
`

`

`CONTENTS XI
`
`Generic Substitution/489
`FrequentlY Asked Questions/ 49 1
`Learning Questions/492
`References/498
`BibliographY/498
`
`1.6. IMPACT OF DRUG PRODUCT QUALITY AND
`B IOPHARMACìÚTICI ON CLINI-CAL EFF ICACY/501
`Risks from Medicines/501
`Risk Managemeît/504
`Scale-Up and Postapproval Changes (SUPAC) /506
`Product QualitY Problems/ 5 1 1
`FrequentlY Asked Questions/ 5 1 3
`Learning Questions/5 1 3
`References,/514
`
`17. MODIFIED-RELEASE DRUG PRODUCTS/S1S
`Examples of Modified-Release Oral Dosage Forms/516
`Biopharmaceutic Factors/ 51 8
`Dosage Form Selection/ 527
`Advantages E¡nd Disadvantages of Extended-Release Produ cts / 521
`Kine tics of Eïtended-Release Dosage Forms/ 5 2 3
`Pharmacokineúc Simulation of Extended-Release Products/525
`Types of Extended-Release Products/527
`Considerations in the Evaluation of Modified-Release Products/542
`Evaluation of In Via o Bioavailabili ty D ata / 5 41
`FrequentlY Asked Questions/549
`Learning Questions/549
`References,/550
`BitrliograPhY/551
`
`18. TARGETED DRUG DELIVERY SYSTEMS AND
`s tólscF{ NoLoGlcAL PRoDucrs/S s3
`Biotechnologr/554
`Drug Carriers and -largeting/662
`Targeted Drug Delivery / 567
`Pharmacokinetics of Biopharmaceuti cals / 569
`Bioequivalence of Biotechnology-Derived Drug Products/571
`
`J7
`
`Sawai (IPR2019-00789), Ex. 1047, p. 009
`
`

`

`¡-
`
`!
`
`XIT
`
`CONTENTS
`
`Frequently Asked Questions/571
`Learning Questions/572
`References/572
`Bibliography,zST3
`
`19. RTLATIONSHIP BETWEEN PHARMACOKINETICS AND
`PHARMACODYNAMIC5/575
`Pharmacodynamics and Pharmacokinetics/575
`Relation of Dose to PharmacologicEffect/577
`Relationship between Dose and Duration of Activity (13¡¡), Single Intravenous
`Bolus Injection/580
`Effect of Both Dose and Elimination HalÊLife on the Duration of
`Activtß//5Bz
`Effect of Elimination HalÊLife on Duration of Actiwty/582
`Rate of Drug Absorption and Pharmacodynamic Response/587
`Drug Tolerance and Physical Dependency/588
`Hypersensitivity and Adverse Response/589
`Drug Distribution and Pharmacologic Response/590
`Pharmacodynamic Models/593
`Frequently Asked Questions/608
`Learning Questions/608
`References/609
`Bibliography/610
`
`20. APPLICATION OF PHARMACOKINETICS IN
`CLIN ICAL S ITUATION5/613
`Individualization of Drug Dosage Regimens/61 3
`Therapeutic Drug Monitonng/ 614
`Design of Dosage Regimens/623
`Conversion from Intravenous Infusion to Oral Dosing/624
`Determination of Dose/626
`Effect of Changing Dose and Dosing Interval o. Cff*, Cffin, and C#/OZA
`Determination of Frequency of Drug Administration,/629
`Determination of Both Dose and Dosage lntewal/630
`Nomograms and Tabulations in Designing Dosage Regimens/631
`Determination of Route of Administration/633
`Dosing of Drugs in Infants and Children/634
`Dosing of Drugs in the Elderly/636
`
`Sawai (IPR2019-00789), Ex. 1047, p. 010
`
`

`

`coNrcNrs XIII
`
`Dosing of Drugs in the Obese Patient/640
`Pharmacokinetics of Drug Interactions/642
`Inhibition of Drug Metabolism/645
`Inhibition of Biliary Excretion/647
`Induction of Drug Metabolism/648
`Altered Renal Reabsorption Due to Changing Urinary pH/648
`Inhibition of Drug AbsorPtion/649
`Effect of Food on Drug Disposition/649
`Adverse Viral Drug Interactions,/649
`Population Pharmacokinetics/650
`Regional Pharmacokinetics/664
`Frequentþ Asked Questions/665
`Learning Questions/ 665
`References,/668
`Bibliography/670
`
`21.. DOSE ADJUSTMENT lN RINAL AND HEPATIC DISEASE/673
`Renal Impairrnent/673
`Pharmacokinetic Consid erations / 67 3
`General Approaches for Dose Adjustment in Renal Disease/675
`Measurement of Glomerular Filtration Rate / 67 7
`SerumCreatinineConcentrationandCreatinineC|earance/678
`Dose Adjustment for Uremic Patients/683
`Extracorporeal Removal of Drugs/696
`Effect of Hepatic Disease on Pharmacokinetics/705
`Frequently Asked Questions/? 1 2
`Learning Questions/71 3
`References,/714
`BibliograPhY,/715
`
`22. PHYSIOLOGICAL PHARMACOKINETIC MODELS' MEAN
`RESIDENTTIME,ANDSTATISTICALMOMENTTHEokY/7|7
`Physiologic Pharmacokinetic Models/718
`Mean Resid ence Tirne / 7 3l
`Statistical Moment "fheory / 7 36
`Selection of Pharmacokinetic Models/751
`Frequentþ Asked Questions/ 754
`Learning Questions/754
`
`travenous
`
`]#/øza
`
`Sawai (IPR2019-00789), Ex. 1047, p. 011
`
`

`

`XIV coNrrNrs
`
`-
`
`-
`
`References,/755
`Bibliograpy/756
`Aþþendix A Statistics/757
`Append,ix B Aþþtications of Comþuters in Pharmacohi'netics/775
`Aþpend,ix C Ethicat Consi'derati'ons/791
`Appendix D solutions to Frequentþ Asked Questions (FAQ) and Learning Questions/g57
`Apþenrtix E Poþular Drugs and' Pharmøcokinetic Parametus/863
`Index/869
`
`lçr
`
`Sawai (IPR2019-00789), Ex. 1047, p. 012
`
`

`

`\9
`
`RELA|IONISHIP
`BETWEENI
`PHARMACOKINIETICS
`ANID
`PHARMACODYNIAMICS
`
`PHARMACODYNAMICS AND PHARMACOKINETICS
`
`Previouschaptersinthisbookhavediscussedtheimportanceofusingpharmaco-
`kinetics to develop dosing regimens that will result in plasma concentrations in the
`rherapeuric windåw and lelã the desired therapeutic or pharmacologic response'
`The interaction of a d.rrg molecule with a receptor causes the initiation of a se-
`quence of molecula. "u.ät resulting in a phaimac.odr¡namic or pharmacologic
`,"rporrr.. The term þharmacod,ynamiclrefers to the relationship between drug con-
`centrations at the site of action (receptor) and pharmacologic response' including
`the biochemi.ui u.ra physiologic effeåts that influence the interaction of drug with
`the recepto r. nuÃy pná-u.äogic research demonstrated that the pharmacody-
`namic ,.rpot* píoà"tta by thã drug depends o1 the chemical structure of the
`drug molËcul.. órrrg receptårs interaðt o.tty øttr drugs of specific chemical struc-
`ture, and the recepio., .''.ir. classifìed according to the type of pharmacodynamic
`resPonse induced.
`since most pharmacologic responses are due to noncovalent interaction between
`thedrugandtherecePtor,thenatureoftheinteractionisgenerallyassumedto
`be reversible and conforms to the Law of Mass Action. one or several drug mole-
`cules may interact simultaneously with the receptor to Produce a pharmacologic
`response. Typically, a single drug molecule inteiacts with a receptor with a single
`binding site io prád,r.. a pharmãcologic response, as illustrated below.
`
`575
`
`Sawai (IPR2019-00789), Ex. 1047, p. 013
`
`

`

`RËLATIONSHIP BETWEEN PHARMACOKINETICS AND PHAW¡.CODYNAMICS
`
`576 cFIAPTERIe
`fDrugì * freceptor] e [druyreceptor complex] -) response
`wherethebrackets[]denotemolarconcentrations,Thisschemeillustratesthe
`occupationtheoryandth.i,,t.,u.tionofadrugmoleculewithareceptormolecule'
`The following assumptions are made in this model'
`l.Thedrugmoleculecombineswiththereceptormoleculeasabimolecularas-
`sociation, and the resulting drug-receptor cãmplex disassociates as a unimolec-
`ular entitY.
`2. in. Ui.tditg of drug with the receptor is fully reversible'
`3. The basic model u"î*"' a single t¡pe of receptor-binding site' with one bind-
`ing site p., ,.."pto' molecule'-It t àtso assumed that a receptor with multiple
`;i;, *"; be moãeled after this (Taylor and Insel' 1990)'
`Itisassumedthattheoccupancyofthedrugmolecule.atonereceptorsitedoes
`not change the affinrty"o;;;;t drug moleculãs to complex at additional receptor
`sites. However, the *á¿"t is not suit"able for drugs ,,r'th auosteric binding to recep-
`tors, in which the binding of one drug molecule to the receptor affects the bind-
`as î" the case of oxygen molecules binding to
`ing of subsequent d;;;;"i"t"le''
`ironinhemoglobin.A.-o,.receptorsareoccupiedbydrugmolecules,agreater
`pharmacodynamic t"õ;;;; is obàned until a maximum response is reached'
`Thereceptoroccupancyconceptwasextendedtoshowhowdrugselicitaphar-
`macologic response ui un'ogonut, åt p'odt"e an opposing pharmacologic response
`às an antergo??rs¿ rhro;;; ã..ig-*..pior interactions. Basically, three types of related
`responses *uy o...t'i'ir'""ttttpior: (1) a drug molecule that interacts with the
`receptor and elicits à -."i-"f phur-u.ologic reiponse is referred to as an agonist;
`(2) a drug that elicits a partiai (below maiimal) response is termed a partial ago-
`nist;and(3)anagenttùtelicitsnoresponsefromihereceptor,butinhibitsthe
`receptor interactiorrãf a second agent, is termed an antagon'isr. An antagonist may
`preventtheactionofanagonist-þcompetitive(reversible)ornoncompetitive
`(irreversible) inhibition'
`Sþare,uttoccupiedreceptorsareasstrmerltobepresentatthesiteofaction,be-
`tTlljï
`cause a maximal pharmacologic response may be óbtained when only "
`tion of th. ,...pto., u." o..ipi.d ïy drug molecules. Equimolar concentratlons
`of different arr,g ,rrot...rlcs thàt normally Ëirr.J t., the same receptor may give diÊ
`ferentdegreesofpharmacologicresponse.Thetermintrinsi'cactiaityisusedtodis-
`tinguish tft. ,elutivt txte"t of ihut*äcologic response betrveen different OilT::l
`ecules that bind ,o ,rr" same receptor. The þotenc) of a drug is the concentratlon
`pharmåcologic effect' such as the ECq'o (see
`of drug needed to o¡tui" u 'ptciht
`.Ç,u" model, below) '
`Thereceptoroccupationtheory,however,wasnotconsistentwithallkineticob.
`servations. An alternative theory, known as lhe rate theory, essetlsally states that the
`pharmacologi. ,"rfã"" is not dependent on drug-receptor complex concentra-
`rion bur rather dd;;ã, on rhe .ut. of association of the drug and the receptor'
`Eachtimeadrugmolecule..hits,'arecePtor,aresponseisproduced,similartoa
`ball bouncing back and forth from rhe ,ä."p,o, sitä. tn. raie theory predicts that
`anagonistwillassociaterapidlytoformareceptorcomplex'whichdissociatesrap-
`antagonist urro.iu,., rapiåty to form a receptor-drug
`r.;;;r..L
`idly to produce
`"
`.oâptå* and dissociates slowly to maintain the antagonist response'
`
`Sawai (IPR2019-00789), Ex. 1047, p. 014
`
`

`

`JVTICS
`
`ates the
`,olecule.
`
`cular as-
`nimolec-
`
`rne bind-
`multiple
`
`site does
`receptor
`to recep-
`the bind-
`rinding to
`a greater
`:ached.
`cit a phar-
`l response
`, ofrelated
`s with the
`an agonßt;
`þartial ago-
`nhibits the
`gonist maY
`:ompetitive
`
`action, be-
`L small frac-
`centradons
`ray give dif-
`used to dis-
`rt drug mol-
`ncentfation
`e ECse (see
`
`ú kinetic ob-
`ates that the
`K concentfa'
`he recePtor'
`, similar to a
`predicts that
`ìsociates raP-
`:cePtor-dru9
`
`RELATIONSHIP BETWEEN PHARMACO KINETICS AND PHARMACODYNAMICS CTIAPTERIS. 577
`Both theories are consistent with the observed saturation þi'gmoidal) drug-dose
`response relationships, ¡rri n.itn.r theory is sufficientþ advanced to give a detailed
`description of the "tock-and-key" or the more recent';induced-fit" type of drug in-
`teractions with enz,rrmatic receptors. Newer theories of drug action are based on
`i.n-uitro studies on isolated tissue receptors and on observation of the conforma-
`tionalandbindingchangeswithdifferentdrugsubstrates'Thesein-ai'trostudies
`show that other types of iäteractions between the drug molecule and the receptor
`are possible. Ho*"u"r, ihe results from the in-aitro studies are difficult to extrapo-
`late to in_aiaoconditiáns. The pharmacologic response in drug therapy is often a
`producr of physiologi.lJuptutiàtr to a drug"rerpot t.. Manf.{r1qs trigger the phar-
`macologic response tt r""gn a cascade of ãnzymatic events highly regulated by the
`body.
`Unlike pharmacokinetic modeling, pharmacodpramic modeling can be more
`complex because the clinical "t"u""ã lchange in blood Pressure or clotting time)
`is often a surrogate f";rh; drug's actua-l phaimacologic àction. For example, after
`the drug i, *yrt.-i.utty u¡ror'å, i, is thËn transportãd to site.of action where the
`pharmacologic receptor resides' Drug-recepto' bi"dittg lal thln cause a second-
`ary response, ,rr.h u, Jgnal transduJtiot" -n'hith then produces the desired effect'
`Clinical measurement of drug resPonse may only occq aftellany such biologìc
`pharmacody-
`events, such as ,rurrrplr, o, ,igrr.t',runrd..-,.iion (an indirect uffutù,
`"o
`namic modeling **, u..o,rrî, for biologic processes involved in eliciting drug-
`
`REI-ATION OF DOSE TO
`PHARMACOLOGIC EFFECT
`
`Theonset,intensity,anddurationofthepharmacologiceffectdependonthedose
`and the prrur*u.oí.inetics of the drug. As the dose, increases, the drug concentra-
`tion at the receptor site increases, arrd"the pharmacologjc response (effecÐ increases
`up ro a ,"*iÃî- effect. A plot of the pharmacologic effect to dose on a linear
`scale generally results in a hyperbolic cuwe with mãximum effect at the plateau
`(Fig. 1g_1). Ti. rum. datamày be compressed and plotted on a log-linear scale
`anã results in a sigmoid curve (Fig' 19-2)'
`
`Sawai (IPR2019-00789), Ex. 1047, p. 015
`
`

`

`578
`
`cHA-PTER 19. RËLÀTtoNSHtP B F.T\,VE E N P H ARr!1,{CO Kl N ET I C S ÀN D P HARÑ1r\CO DYNAlvtl CS
`
`Mox
`response
`
`A smoll increose in
`response,occurs by
`o grven dose chonqg
`
`A lorge ìncreose in
`resoonse occurs by
`o oiuen dose chonge
`in lhis region
`
`Drug dose
`
`ocooo
`
`.9oo
`
`ooEo<d
`
`Figure 19-1 . PIot of pharmacologic re-
`sponse versus dose on a linear scale.
`
`Fo. many drugs, the graph of log close-response cLuve sholvs a linear relation-
`sl.rip at o dor" ,uãg" b.t*" in 20Vo and B0% of the ma¡mlrm resPonse, r'vhich typ-
`icaily includes the therapeutic close range for many clrugs. For a drug that follo'vs
`or,r.l.o*pn.tment pharmacokinetics, the volrtme of distribution is constant; lhere-
`fore, the pharrnacålogic response is also proportional to the log plasma d^rg con-
`centrado; lvithin a therapeutic range' as shor'vn in Figure 19-3'
`Nfathematically, the re-lationship in Figure 19-3 may be expressed by the foilow-
`ing equation, r,vhere rz is the slope, ø is an extrapolatecl intercept, and -E is the drug
`effect at drug concentration C:
`E:'mIogC-r e
`
`(19"i)
`
`(ne"2)
`
`Slope = m
`
`oo
`
`Solving for log C Yielcls
`E- e
`loeC:-
`"m
`
`.9
`
`ÐoooEo
`
`IÈ
`
`Log drug concenlrotion
`
`Figure 19-3. GraPh of log drug con-
`centrat¡on versus pharmacologic effect
`Only the line¿r port¡on of the curve ls
`shown.
`
`^4.
`
`oo
`
`.D
`oõ
`
`oE Õ
`
`Iù
`
`Log dose
`
`Figure 19-2. Typical log dose versus
`pharmacologic resPonse curue.
`
`Sawai (IPR2019-00789), Ex. 1047, p. 016
`
`

`

`RÈLATIONS HIP BETWEEN PHARM,{CO KINËTI CS AND P HARMACO DYNAMICS CFI,APTER 19
`However, after an intr
`one-comparrmenr ô:ii#ì
`IogC: logCr-
`
`Î."å::låï::'åî:*:l of a drug in the body in a
`
`579
`
`(re.3)
`Equarion 1e.3, we ger Equatio n te. ,where
`
`(Ls.4)
`
`kt
`2.3
`
`2+
`By substituting Eoual
`¿, = "rr;;;;':;:;iffi|,ofå,'","
`E- e Eo- e
`tll
`rn
`E=E¡-hmt
`- 2.3
`The theoreticar pharmacorogic response at anytime after an inffavenous dose
`it #å,îåL .","1;;f'*.n:liuil"'. ro +lq"ìtäîìón predicts trrat tne
`1: :,,,n;, *' ï;, i"i:i;'ffi i : #ir.:l:ï::l*: I 1il r
`c om p ar tm e n, *
`o
`equation, the pharmacotogic
`"
`"n .t ¿"?1i.,.: trh ^ rl"på"ãi7i12.3. The decrease
`rn pharmacorogic etr1c1 is'rff;iä;;iotr,
`t1.,. "il;,l;;;,,Jon.,u,,, h and. the
`slope zz' For a drus-with a u.ìs;
`åi il-1.*"corogic response decrines rapidrv
`andrurtipre doses musr be givËn at ,ho.i i't.*uk rJmuintärlìn" prru._u.oiogiá
`^
`The relationshin between pharmacokinetics and pharmacologic response can
`be demons trated bv :br"*;g'rh; Ë.# a.p..r.iã.,' àTffi ;ì;, ac tivi ry arrer an
`ü:i:î :i^Í?"1lå:ïll*hîiñ". "r,0n..*.;;ü;.m.., i, rinea. a, u
`th e srope or .u.r,' .ï*. i, tr,.,um..'üïi..îïli:i å1"#i.:,:Ë: iïLr",,;.
`clude hm (Eq' r9'a),,are.rhe ru-., ,tã r.rridviE of il;**;ä;, ror (*)_tubocu_
`rarine is assumed to be the,il;;r;;'.h lir. oru.con. Nore rhar.
`concentration of drug v_ersus time yields a straight line.
`a plot of the log
`A second ou-pr.îr,t.il]ää*ii*J
`observed with lysersic a.ia ji.*,yram;;;ï, rso 1rig. iô_?1..*ä. an rV dose of
`**
`d_ecrining rinearry with time was
`:l'ËTrJii::.iïïîi:;:il:*#ï*.arnea.r-vøil;;;".."p,rorabrier
`p e rrorman c.'. o," or
`*i'," üj*,ä J'åiiï:t i,iïff *J',,iïî:: r":r,,i:
`
`-
`
`"
`
`t7-+. Depression of normal rnuscle activirv
`It-Syr;e
`as a funcrion of time after tV a¿m¡nistrati;; o:ì:ål.l
`mg /+)-rubocurarine per kilogram ;;;;#;,##;
`volunteers, presentjng me¿
`on s suolelts.-ënî,J, "'c¿n values of ó experimenß
`7 ! a s ri p ; ";; *;il.'fl,i;:,: f i,Zl::o'
`", uti, ts6+, *,il'permission.¡
`
`l,{dapred from JohanËn
`
`sq ua res,
`
`20
`
`lo
`
`I 5
`{minutes)
`
`{ T
`
`ime
`
`00
`
`AMIC
`
`Mox
`
`_response
`Lcræse in
`cccurs bv
`rse choíge
`
`relation-
`hich typ-
`Lt follows
`rt; there-
`lrug con-
`
`,e follow-
`the drug
`
`(le.l)
`
`(re.2)
`
`e=m
`
`on
`
`drug
`
`1e cuNe
`
`Sawai (IPR2019-00789), Ex. 1047, p. 017
`
`

`

`580
`
`CIIAPTER19.
`
`RTLATIONSHIP BETWEEN P HARMACOKIN ETICS AND PHARMACODYNAMICS
`
`l0
`
`5
`
`2
`
`B E Ê Éoo o o oEqE
`
`0
`
`2
`
`4
`Time (hours)
`
`6
`
`I
`
`0
`
`2
`
`A
`
`6
`
`8
`
`Time (hours)
`
`0
`
`20
`
`40
`
`ó0
`
`80
`
`00
`
`Aõco ococoo
`
`-
`
`oÇoEo
`
`to
`
`t;
`
`i
`
`ri
`
`Figurelg-5'MeanplasmaconcentrationsofLsDandpefformancetestscoresasafunctionoftime
`after lV u¿tin¡'t'utïá'i *' *n LSD per kilogram to 5 normal human subjects'
`{Adapted from nffinian unialng' 1964'witn permission )
`
`slopeisgovernedinpartby.the'eliminationrateconstant,thepharmacologiceffect
`declinesmuchmorerapidlywhentheeliminationrateconstantisincreasedasa
`resultofincreasedmetabolismo,,"'urexcretion.Conversely,alongerpharma-
`cologic ,.rporri. i, experienced in puü.",r when the drug has a longer halÊlife'
`
`RELATIONSHIP BETWEEN DOSE AND DURATION
`OF ACTIVITY (¿"rr), SmCfn W BOLUS INJECTION
`The relationship between the.duration of the pharmacoloSic ef'fec1 "11:1t':"t'
`canbeinferredfromEquationlg.S.Afterãnintravenousdose,assumrnga
`one-compar'*t"tmodel'thetimeneededforanydrustodeclinetoacon-
`centration c is given by the following equation, assumin! the drug Þkes effect
`
`immediatelY:
`2.3 (log Cs - log C)
`t:
`Usins Úì.¡¡ to represent the minimum effective drug concentration' the duration of
`ã.rrg"u.,ior, .ut bt obtained as follows:
`
`(1e.5)
`
`h.
`
`2.3lrog(Do/ V¡) - log C.6]
`k
`
`t.tr
`
`(1e.6)
`
`Some practical applications are suggested by this equation' For example ' a do1)'
`in a ääubli"g or the effective duration of pharma-
`bling of the dose *tu ;;;;;;t
`cologic acrion. o" rh;^;rh; hund, a doublin"g of \¡2or a c.orresponding decrease
`in É will resulr in u prof-,ional increase i"'àir"ri." of action' A ctinical situadon
`which c"ris the bacteriocidal
`is often encounrered;ï* äui.;itrl"r..,îå"tin
`concentrarion of the drug, and, in order t" ãã,r¡r. the duration of the antibiotic'
`a considerabry g"u"' i":tease than simply doubling the dose is necessary'
`
`Sawai (IPR2019-00789), Ex. 1047, p. 018
`
`

`

`lvtlCS
`
`RTLATIONSHIP BETWEEN PHARMACOKINETICSAND PHARMACODYNAMICS CHAPTERlg, 581
`
`PRACTICE PROBLEM
`
`The minimum effective concentration (MEC) in plasma for a certain antibiotic is
`0.7 y,g/mL. The drug follows a one-compartment open model and has an apparent
`volume of distribution, V¡, of 10 L and a first-order elimination rate constant of
`1.0 hr-1.
`a. What is the /.¡¡ for a single 100-mg fV dose of this antibiotic?
`b. What is the new t ç oÍ tt¿çç for this drug if the dose were increased lO-fold, to
`1000 mg?
`
`Solution
`a. The ú.ç for a 100-mg dose is calculated as follows. Because Vo : 10,000 mL,
`co : ro¡ooä : 1o P'g/mL
`100 ms
`For a one-compartment-model IV dose, C : Coe kt. Then
`0.1 - 10ø-(1.0),.r
`ú.6: 4.61 hr
`
`b. The f'"s for a 1000-mg dose is calculated as follows (prime refers to a new dose)
`Because Vo : 10,000 mL,
`1000 ms
`Có = 10¡00Ë
`and
`
`: 100 þS/mL
`
`Ct u: Q'og-|'tk
`0.1 :100¿-(t.o),:r
`tir: 6.91 hr
`
`The percent increase in f.6 is therefore found as
`
`x loo
`Percent increase in ¿.n:
`"#
`Precent increase in r- : 6'91 - 4'6r x 100
`/\
`| úeff -
`4.6r
`Percent increase it t ç: 50Vo
`This example shows that a lO-fold increase in the dose increases the duration of
`action of a drug (t rr) by only 50Vo.
`
`I
`
`¡n of time
`
`jc effect
`sed as a
`pharma-
`alÊlife.
`
`the dose
`uming a
`o a con-
`.es effect
`
`(1e.5)
`
`rration of
`
`(1e.6)
`
`le, a dou-
`I pharma-
`: decrease
`situation
`:teriocidal
`lntibiotic'
`ry.
`
`Sawai (IPR2019-00789), Ex. 1047, p. 019
`
`

`

`582
`
`CHAPTER19. RËLA TIONSHTP BETWEEN P HARMACOKINETICS AN D PHARMACODYNAMICS
`
`EFFECT OF'BOTH DOSE AND ELIMINATION
`TIALF.LIFE ON TFIE DUR.ÄTION OF ACTTVTTY
`Asingleequationcanbederivedtodescribetherelationshipofdose(Do)andthe
`elimination rráürir" (t1¡2) onrhe effective time for therapeutic activity (tn)' This
`exPrcssion is derived below'
`ln C.¡¡ - lnCo - kt.n
`Because Cç : Dç/ V¡¡,
`tn c"' : t"(+) - kr,o
`\ Vnl
`ur.,,: r,'(o;) - t" **
`\ Vol
`1 / Dn/ V"\
`t.s: i,"\ a* /
`Substituting 0'693 / \72 for h'
`./4\
`t"¡: l'44tr,tt"\yrc*/
`From Equation 19.8, an increase in \72 will increase the f'¡¡in direct pfopor-
`tion. However, un irr.r.ur. in the dose, D9, does not increase the f.¡¡ in direct pro-
`portion.Theeffectofanincreasein,Vp"orCgffcalbeseenbyusinggenerated
`data. Only ,n. f"rtilr. solurions for Eqtiation 19.8 are valid, although mathemati-
`cally a ,r.suüu.".r, can be obtained by increasiirg c"n or v¡. The effect of chang-
`ing dose on ¿.m i, ,t o*r, in Figure 1916 using data generated with Equation 19'8'
`A nonlinear it""ut" in lt¡¡ is obsewed as dose increases'
`
`(1e'?)
`
`(1e.8)
`
`EFFECT OF ELIMINATION HALF-LIFE
`ON DURATION OF ACTTVITY
`
`Becauseeliminationofdrugsisduetotheprocessesofexcretionandmetabolism'
`an alteration of any of these eliminJon p.o."rr.r.rill effect t¡,e \¡2 of the drug'
`In certain disease states, pathoptrysioÇic'changes in hepatic or renal function will
`
`6 4
`
`2
`
`)o
`
`I
`
`Figwe 19-6. Plot of f"¡¡ versus dose'
`
`4
`
`a12
`Dose (mg/kg)
`
`16
`
`Sawai (IPR2019-00789), Ex. 1047, p. 020
`
`

`

`)YNAMiCS
`
`iDs) and the
`y (r.rr). This
`
`(1e.7)
`
`(1e.8)
`
`lirect propor-
`in direct pro-
`ing generated
`çh mathemati-
`fect of chang-
`lquation 19.8.
`
`rd me
`/z of the
`al functton
`
`Dose
`
`R-ELATIONSHIP BETWE
`
`EN PHARMACO KINETICS AND PHARMACODYN AMICS CFTAPTERlg.
`583
`decrease the elimination of a d.rug, as observed by a prorong ed. t1¡2.This prolonged
`\72 vnll lead to rerenrion of the irug in the body, thereby increasing the duration
`of activity of the drug (r.¡¡) as well ui in.r.uringll-...n".rín'iÇ
`"r a."g toxicity.
`To improve antibiotic therapy with the oenicilrin and cephalosporin antibi_
`otics, clinicians have intentionåliy p.oto.,g.a the eriminatiori or these drugs by
`giving a second drug, probenecíá,'which competitively inhibits renal excretion
`of the antibiotic. This åpproach to proronging the duration ãì.activiry of antibi_
`otics that are rapidlyexcreted through tne t ialney rru, ¡..r, ,rr.d ,r...rrfrlly for
`a number of years. similarly, Augm"entin is a cåmbinutior, ãr amoxicillin and
`clamlanic acid; the ratter is an inhîbitor of B-lactamase. This B-lactamase is a bac_
`terial enzyme that degrades penicillin-like drugs. Th. d.; i;i"¡r. 19.1 illustrate
`how a change in rheili-irråtior, ,rrr*rtlaffeãt the ,.rrfo;; ã.,rg. ro. all doses,
`a 100% increase in the fi72vør..rrrll in u toovo increäe in trr. r.¡¡. For example,
`for a drug whose t172
`0.7bhour and. that is given at u aor. o¡ z mg/kg,the /.¡¡
`is 3'24 hours. rf the t172is increased to r.5 hours, the l.¡¡ is increased to 6.4g hours,
`'s
`an increase of r00vo. However, rhe effecr of doutrling;ir. ;;;. i."m 2 to 4 mg/kg
`(no change in elimination processes) wilionryincrease the l.¡¡to 3.gB hours, an
`increase of 22.Bvo. The efiect of prolonging rhe eliminatiän halÊlife has an
`extremely important effecr on th. treatm.rrt oi infectiorrr, furiil"rurly in patients
`with high metabolism, or clearance, of the antibiotic. Therefore, antibiotics must
`be dosed with full considerarion of the .n"., àl"ii;ää;
`e t1¡2 onrhe /.¡¡.
`consequently, a simple proporrional increase in dose *ü1.;
`in. puti..rt,, blood
`concentration below the effective antibiotic lever most or tt.-ti*. during drug
`therapy' The effect of a proronged t r¡ i" ,ho*r, in rines o inJ. ,in Figure rg_7,
`and. the disproportionate increaã. inl"rras rhe dose is irr...u*¿ rO_fold is shown
`in lines a and b.
`
`ÏABLE
`
`'9.I
`
`Relationshíp between Elimjnation Half_Life and Duration of Act¡vity
`ttn = O.75 hr
`DOSE
`fi2: 1.5 hr
`lmglkgl
`f"6 {hrf
`f"n {hrl
`2.0
`) 1À
`6.48
`3.0
`7.35
`4.0
`7.97
`5.0
`8.45
`6.0
`B.84
`7.0
`Lt8
`8.0
`9.47
`9.0
`9.72
`t0
`9.9s
`il
`10.2
`I2
`10.3
`l3
`10.5
`14
`10.7
`t5
`t0.B
`to
`I 1.0
`ll.r
`17
`1t .2
`r t.3
`1I .4
`
`3.67
`3.98
`4.22
`4.42
`4.59
`4.73
`4.86
`4.97
`5.08
`5.t7
`5.26
`5.34
`5.41
`5.48
`5.