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`ANDREW B.C. YU MPI EXHIBIT 1045 PAGE 1
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`i|
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`i
`ie
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`!
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`PaUEhes
`
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`aati
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`Ra ae
`SUSANNA WU-PONG
`
`MPI EXHIBIT 1045 PAGE 1
`
`

`

`
`
`The McGraw·H/11 Companies
`
`· •
`
`
`
`Applied Biophannaceutics and Phannacokinetics, Fifth Edition
`
`
`
`Copyright© 2005 by The McGraw-Hill Companies, Inc. Copyright© 1999, 1993 by Appleton
`
`
`
`
`
`
`
`
`& Lange; copyright© 1985, 1980 by Appleton-Century-Crofts. All rights reserved. Printed
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`
`in the United States of America. Except as permitted under the United States copyright
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`
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`Act of 1976, no part of this publication may be reproduced or distributed in any form or
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`by any means, or stored in a data base or retrieval system, without the prior written per­
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`mission of the publisher.
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`
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`7 8 9 0 DOC/DO 0
`
`ISB 0-07-137550-3
`
`This book was set in New Baskerville by TechBooks.
`
`
`
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`The editors were Michael Brown and Christie Naglieri.
`
`The production service was TechBooks.
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`Th production supervisor wa Phil Galea.
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`The cover d signer was Kelly Parr.
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`RR Donnelley was printer and binder.
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`This book i printed on acid-free paper.
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`
`Library of Congress Cataloging-in-Publication Data
`
`
`
`Applied biopharmaceutics & pharmacokinetics/Leon Shargel, Susanna Wu-Pong,
`
`Shargel, Leon, 1941-
`
`
`
`
`Andrew B.C. Yu. -5th ed.
`p.; cm.
`Includes bibliographical references and index.
`
`
`
`ISB 0-07-137550-3
`
`
`
`
`
`
`II. Wu-Pong, Su anna. III. Yu, Andrew B. C.,
`pharmacokinetics.
`1945-IV. Title.
`
`
`
`
`QV 38 S53la 2004) R.t\lI301.4.S52 2004
`6J5'.7-dc22
`
`l.Biopharmaceutics. 2. Pharmacokinetics. l. Title: Appli.ed biopharmaceuLics and
`
`[DNLM: l. Biopharmaceutics. 2. odels, hemical. 3. Pharmacokinetics.
`
`2004044993
`
`Please tell the authors and publisher what you think of this book by sending your
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`comments to phannacy@mcgraw-hill.com. Please put the author and title of the
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`book in the subject line.
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`MPI EXHIBIT 1045 PAGE 2
`
`

`

`>
`
`· Appleton
`d.Printed
`copyright
`1y form or
`ritten
`per-
`
`1 Wu-Pong,
`
`:eutics
`and
`
`tics.
`
`2004044993
`
`:nding your
`title of the
`
`CONTENTS
`
`Preface/XV
`Glossary I XVII
`
`1.INTRODUCTION
`TO BlOPHARMACEUTICS
`AND
`PHARMACOKINETLCS/1
`
`Biopharmaceutics/
`1
`Pharmacokinetics/
`3
`Clinical
`Pharmacokinetics/3
`Pharmcodynamics/ 4
`Toxicokinetics
`and Clinical
`Toxicology/
`4
`Measurement
`of Dmg Concentrations/5
`Basic Pharmacokinetics
`and Pharmacokinetic
`Models/9
`References/18
`Bibliography/
`18
`
`2.MATHEMATIC
`FUNDAMENTALS
`[N
`PHARMACOKlNETICS/21
`
`Math Self-Exam/21
`Estimation
`and the Use of Calculators
`and Computers/22
`Calculus/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
`
`MPI EXHIBIT 1045 PAGE 3
`
`

`

`VI CONTENTS
`
`3.ONE-COMPARTMENT
`OPEN MODEL: lNTRAVENOUS
`BOLUS ADMINISTRATION/51
`
`Elimination Rate
`Constant/52
`Apparent Volume
`of Distrib
`ution/53
`Clearance/57
`C alculation
`of K from Urinary
`Excretion
`Data/63
`Fr quently
`Ask d Questions/69
`Learning Questions/69
`Reference/72
`Bibliography/72
`
`4.MULTICOMPARTMENTAL
`MODELS: INTRAVENOUS
`BOLUS ADMlNlSTRATlON/73
`
`Two-Compartment
`Open Model/75
`Three-Compartment
`Open Model/93
`Determination
`of ompartment
`foclels/95
`Frequently
`Asked Questions/101
`Learning
`Questions/102
`References/
`105
`Bibliography/105
`
`5.INTRAVENOUS
`lNFUSlON/105
`
`One-Compartment
`Model Drugs/108
`Infusion
`Method for Calculating
`Patient
`liminati
`on Half-Life/112
`Loading
`Dose Plus IV Infusion:
`One-Compartment
`Model/115
`Estimation
`of Drug Clearanc
`and Vo from Infusion
`Data/122
`Intraveno
`us Infusion
`of Two Compartment
`Model Drugs/122
`Loading
`Do e Plus IV Infusion:
`Two-Compartment
`Model/123
`Frequently
`ked Questions/127
`L arning Question
`/127
`Reference
`/129
`Bibliography
`/129
`
`6.DRUG ELIMINATION
`�D CLEARANCE/131
`
`Drug Elimination/
`131
`The Kidney/132
`
`MPI EXHIBIT 1045 PAGE 4
`
`

`

`CONTENTS Vll
`
`Renal Drug Excretion/136
`Drug Clearance/139
`learance
`Models/142
`Renal Clearance/144
`Determination
`of Renal Clearance/149
`Relationship
`of Clearance
`to Elimination
`Half-Life
`and Volume of
`Distribution/155
`Frequently
`Asked Question
`/157
`Learning
`Questions/158
`References/
`159
`Bibliography
`/159
`
`7.PHARMACOKINETlCS
`OF ORAL ABSOR.PTION/161
`Pharmacokinetics
`of Drug Ab orption/161
`Zero-Order
`Absorption
`Model/163
`First-Ord
`r bsorption
`Model/164
`Significance
`of Absorption
`Rate Constants/181
`Frequently
`Asked Que tions/182
`Learning
`Questions/182
`Reference
`/184
`Bibliography/184
`
`8.MULTIPLE DOSAGE R.EGlMENS/185
`Drug ccumlation/185
`R petitive
`Intravenous
`lnjections/190
`Intermittent Intravenous
`Infusion/197
`Estimation
`of k and Vo of Aminoglycosides
`in Clinical
`Situations/201
`Multiple-Ora
`l-Dose
`Regimen/202
`Loading
`Dose/205
`Determination
`ofBioavailability
`and Bioequivalance
`in a Multiple-Dose
`Regimen/207
`Bioequivalence
`Studies/208
`Dosage Regimen Schedul
`s/210
`Frequently
`Asked Questions/215
`Learning
`Qu stions/215
`Reference
`/216
`Bibliography/217
`
`2
`
`MPI EXHIBIT 1045 PAGE 5
`
`

`

`VIII CONTENTS
`
`Drug Elimination by Capacity-Limited Pharmacokinetics: One-ompartment
`
`9.NONLINEAR PHARMACOKlNETICS/219
`
`
`
`Saturable Enzymati Elimination Proces e /221
`
`
`
`
`Model, Intravenous Bolus Inj ction/224
`Equations for Drugs Distributed as One-Compartment Model and
`
`
`
`
`
`Eliminated by Nonlinear Pharma okinetics/239
`
`
`Bioavailability of Drugs That Follow Nonlinear Pharrnacokinetics/243
`
`
`
`Nonlinear Pharmacokinetics Due to Drug-Protein Binding/243
`Frequently Asked Questions/246
`
`Learning Questions/246
`References/248
`
`Bibliography /248
`
`10.-PHYSIOLOGIC DRUG DISTRIBUT[ON AND
`
`
`PROTEIN BlNDING/251
`
`Physiologic Factor of Distribution/251
`
`Apparent Volume Distribution/259
`
`
`Protein Binding of Drugs/267
`
`
`
`Elirnination/275
`
`
`Determinants of Protein Binding/279
`
`
`Kinetics of Protein Binding/280
`
`
`
`
`Methods/282
`Clinical Significance of Drug-Protein Binding/286
`
`
`
`Modeling Drug Distribution/296
`
`Frequently Asked Questions/297
`
`Learning Qu stions/298
`R ferences/299
`Bibliography/301
`
`
`
`Relationship of Plasma Drug-Protein Binding to Distribution and
`
`Determination of Binding Constants and Binding Sites by Graphic
`
`
`11.HEPATIC ELIMINATION OF DRUGS/303
`
`Route of Drug Administration and Extrah patic Metabolism/303
`Enzyme Kinetics/308
`
`Anatomy and Physiology of the Liver/316
`
`
`
`Hepatic Enzymes Involved in th Biotransformation of Drugs/319
`
`MPI EXHIBIT 1045 PAGE 6
`
`

`

`>artment
`
`:43
`
`CONTENTS lX
`
`Hepatic Clearance of a Protein-Bound Drug: Restrictive and onrestrictive
`
`Pathways of Drug Biotransformation/321
`
`
`First-Pass Effects/332
`
`
`
`
`
`Clearance from Binding/340
`
`
`Biliary Excretion of Drugs/344
`
`Frequently Asked Questions/348
`
`Learning Questions/348
`
`References/ 351
`
`Bibliography /353
`
`12.PHARMACOGENETlCS/355
`
`Genetic Polymorphism in Drug Transport: P-Glycoprotein and Multidrug
`
`
`
`Example of Polymorphisms/356
`
`Pharmacogenomics/359
`Adverse Drug Reactions Attributed to Genetic
`
`
`
`Differences/361
`
`
`
`Genetic Polymorphism in Drug Metabolism: Cytochrome
`P-450
`Isozymes/361
`
`
`
`Resistance/364
`
`
`Genetic Polymorphism in Drug Targets/365
`
`Pharmacokinetics/Pharmacodynamics (PK/PD) Considerations
`and
`
`
`Pharmacogenetics/Pharmacogenomics (PGt/PGx)
`/366
`
`Frequently Asked Questions/367
`References/368
`
`Bibliography /369
`
`13.PHYSIOLOGIC FACTORS RELATED TO
`
`DRUG ABSORPTION/371
`
`Route of Drug Administration/371
`
`Nature of Cell Membranes/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 Absorption/
`401
`
`Frequently Asked Questions/
`405
`
`
`Learning Question / 405
`References/ 406
`
`Bibliography/ 408
`
`9
`
`MPI EXHIBIT 1045 PAGE 7
`
`

`

`X CONTENTS
`
`14.BlOPHARMACEUTlC CONSlDERATlONS lN
`
`
`
`DRUG PRODUCT DESIGN/411
`
`Rate-Limiting St ps in Drug bsorption/413
`
`
`
`Pharmaceutic Factors Affecting Drug Bioavailability/413
`
`Physicoch mica! Nature of the Orug/415
`
`
`
`Formulation Factors Affecting Drug Dissolution/'118
`
`Dissolution and Drug Rel ase Testing/421
`
`Comp ndial Methods of Dissolution/ 424
`
`
`Meeting Dissolution Requirements/428
`
`
`
`Alternative Methods of Dissolution Testing/429
`
`
`
`Probl ms of Variable Control in Dissolution Testing/430
`Correlation/431
`fn-Vitro-In-Vivo
`
`
`Biopharmaceutic Considerations/ 436
`
`
`Pharmacodynarnic Considerations/ 437
`
`Drug Considerations/ 437
`
`Drug Product onsiderations/ 438
`
`
`Patient Considerations/ 439
`
`Route of Drug Administration/ 439
`
`
`Frequently Asked Questions/ 449
`
`Learning Questions/ 450
`
`References/ 450
`Bibliography/451
`
`Design and Evaluation of Bioequivalence Studies/ 467
`
`
`
`15.BlOAVAlLABILlTY AND BLOEQl)LVALENCE/453
`
`Definitions/ 453
`
`
`
`Purpose of Bioavailability Studies/456
`
`
`Relative and Absolute Availability/457
`
`
`Methods for As essing Bioavailability/460
`
`Bioequivalence Studies/465
`
`
`Study Designs/ 4 70
`
`Evaluation of the Data/ 4 73
`
`
`Bioequivalence Example/ 4 75
`
`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 Bioavailabilily and Bioequivalence Studies/487
`
`MPI EXHIBIT 1045 PAGE 8
`
`

`

`CONTENTS XI
`
`Generic Substitution/489
`
`
`
`Frequently Asked Questions/ 491
`492
`
`Learning Questions/
`
`References/ 498
`Bibliography/ 498
`
`16.IMPACT OF DRUG PRODUCT QlJALlTY AND
`ON CLINICAL EFFICACY/501
`BlOPHARMACEUTlCS
`Risks from M dicines/501
`Risk Management/504
`Changes (SUP C)/506
`and Postapproval
`Scale-Up
`
`
`Product Quality Problems/511
`
`Frequently Asked Questions/513
`
`
`Learning Questions/ 513
`References/514
`
`E DRUG PRODUCTS/515
`17.MOD!FlED-RELEA
`Oral Dosage Forms/516
`of Modified-Release
`Examples
`Factors/518
`Biopharmaceutic
`Dosage Form Selection/521
`Products/521
`of Extended-Release
`�d Disadvantages
`dvantages
`Dosage Forms/523
`of Extended-Release
`Kinetics
`Products/525
`of Extended-Release
`Simulation
`Pharmacokinetic
`Products/527
`Types of Extended-Release
`Products/542
`of Modified-Release
`in the Evaluation
`Considerations
`Bioavailability
`Data/547
`Evaluation
`of In-Vivo
`Asked Questions/549
`Frequently
`Learning Questions/549
`References/ 550
`
`Bibliography/ 551
`
`18.TARGETED DRUG DELIVERY SYSTEMS AND
`
`BIOTECHNOLOGICAL PRODUCTS/553
`
`Biotechnology /554
`
`Drug Carriers and Targeting/562
`
`Targeted Drug Delivery/567
`
`
`Pharmacokinetics of Biopharmaceutical /569
`
`
`of Biotechnology-Derived Drug Products/571
`Bioequivalence
`
`37
`
`MPI EXHIBIT 1045 PAGE 9
`
`

`

`XII CONTENTS
`
`Frequ ntly Asked Questions/571
`
`Learning Questions/572
`
`References/ 5 72
`Bibliography/573
`
`•
`
`19.RELATIONSHIP BETWEEN PHARMACOKINETICS AND
`
`Relationship between Dose and Duration of Activity (½rr), Single Intravenous
`
`
`
`PHARMA CO DYNAMI CS/575
`
`
`Pharmacodynamics and Pharmacokin tics/575
`
`
`Relation of Dose to Pharmacologic Effect/577
`
`
`
`
`
`
`Bolus Injection/580
`
`
`Activity/582
`Effect of Elimination Half-Life on Duration of Activity/582
`
`
`
`
`
`Rate of Drug Absorption and Pharmacodynamic Response/587
`
`
`Drug Tolerance and Physical Dependency/588
`
`
`Hyp ersensitivity and Adverse Response/589
`
`
`Drug Distribution and Pharmacologic Respon e/590
`
`Phannacodynamic fodel /593
`
`Frequently Asked Questions/608
`
`Learning Questions/608
`
`References/ 609
`Bibliography/610
`
`
`
`
`
`Effect of Both Dose and Elimination Half-Life on the Duration of
`
`
`
`20.APPLlCATION OF PHARMACOKINETlCS lN
`CLINICAL SlTUATlONS/613
`
`Individualization of Drug Dosage Regimens/613
`
`Therapeutic Drug Monitoring/614
`Design of Dosage Regimens/623
`
`
`
`Conversion from Intravenous Infusion to Oral Dosing/624
`
`Determination of Dose/626
`Effect of Changing Dos and Dosing Interval on C�,x, c:n, and C;/628
`
`
`
`
`
`
`Determination of Frequency of Drug Administration/629
`
`Determination of Both Dose and Dosage Interval/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
`
`MPI EXHIBIT 1045 PAGE 10
`
`

`

`travenous
`
`CONTENTS Xlll
`
`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 lnteractions/649
`
`
`Population Pharmacokinetics/ 650
`
`Regional Pharmacokinetics/664
`
`Frequently Asked Questions/665
`
`Learning Questions/665
`References/ 668
`Bibliography/670
`
`21.DOSE ADJUSTMENT
`lN RENAL AND HEPATIC DISEASE/673
`Renal Impairment/673
`Pharmacokinetic Considerations/673
`
`
`
`General Approaches for Dose Adjustment in Renal Disease/675
`
`
`
`Measurement of Glomerular Filtration Rate/677
`
`
`
`Serum Creatinine Concentration and Creatinine Clearance/678
`
`Dose Adjustment for Uremic Patients/683
`
`Extracorporeal Removal of Drugs/696
`
`
`
`Effect of Hepatic Disease on Pharmacokinetics/705
`
`Frequently Asked Questions/712
`Leaming Questions/713
`References/714
`Bibliography /715
`
`22.PHYSIOLOGICAL PHARMACOKINETIC MODELS, MEAN
`
`
`
`RESIDENT TIME, AND STATISTICAL MOMENT THEORY/717
`
`
`Physiologic Pharmacokinetic Models/718
`
`Mean Residence Time/731
`
`Statistical Moment Theory/736
`
`
`Selection of Pharmacokinetic Models/751
`
`Frequently Asked Questions/754
`Learning Questions/754
`
`MPI EXHIBIT 1045 PAGE 11
`
`

`

`XIV CONTENTS
`
`R ferences/755
`
`Bibliograpy
`/756
`
`Aj;pendix A Statistics/757
`
`Appenclix
`B AP,/Jlications
`of Computers in
`Pharmacokinetics/775
`
`Appendix C Ethical
`Considerations/791
`
`Append-ix
`D Solutions
`to Frequently Asked Questions
`(FAQ) ancl
`Learning Que.stions/857
`
`Appendix E Popular
`Drugs and Pharmacokinetic
`Parameters/863
`
`lndex/869
`
`MPI EXHIBIT 1045 PAGE 12
`
`

`

`INTRODUCTION TO
`BIO PHARMACEUTICS
`AND
`PHARMACOKINETICS
`
`BIO PHARMACEUTICS
`
`All pharmaceuticals, from the generic analgesic tablet in the communi ty pharmacy
`to the state-of-the-art immunotherapy in specialized hospitals, undergo extensive
`research and development prior to approval by the U.S. Food and Drug
`Administration (FDA). The physicochem ical characteristics of the active pharma(cid:173)
`ceutical ingredient (API, or drug substance) , the dosage form or the drug, and the
`route of administration are critical de te rminants of the in-vivo pe rforma nce, afety
`and effi cacy of the drug product. The properties of the drug and its dosage form
`are carefu lly e ngineered a nd tested to produce a stable drug product that upo n
`administration provides the desired the rape utic response in the patien t. Bo th the
`pharmacist and the pharmaceutical scie ntist must unde rstand these complex rela(cid:173)
`tio nships to compre he nd th e prope r use and development of pharmaceuticals.
`To illustrate the importance of the drug substance and the drug fo rmula tion on
`absorp tion, and distribution of the drug to the site of action, one must first con(cid:173)
`sider the seque nce of events that preced e elicita tio n of a drug's therape utic effec t.
`First, the drug in its dosage form is ta ke n by the patie nt either by an oral, intra(cid:173)
`venous, subcutan eous, tra nsde rmal , e tc., route of administration . ext, the drug
`is released from the dosage fo rm in a predicta ble a nd cha rac te rizable manner.
`Then , some fraction of the drug is absorbed fro m the site of administration into
`either the surrounding tissue, into the body (as with o ral dosage fo rms), or both.
`Finally, the drug reaches the site of actio n . If the drug concentratio n a t the site of
`action exceeds the minimum ejprtive concentration (MEC), a pharmacologic response
`results. The actual dosing regi me n (dose, dosage form , d osing interval) was care(cid:173)
`fu lly de termined in clinical trials to provide the correct drug concentration s a t
`1
`
`MPI EXHIBIT 1045 PAGE 13
`
`

`

`2
`
`CHAPTER 1.
`
`INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS
`
`the site of action. This sequence of events i profoundly affected-in fact, some(cid:173)
`times orchestrated-by the design of th e dosage form, the drug itse lf, or both.
`Hi torically, pharmaceutical cient..i ts have evaluated the relative drug availability
`to the body in vivo after giving a drug produc t to a n a nima l or human , and then
`comparing specific pharmacologic, clinical, or possible toxic responses. For ex(cid:173)
`a mple, a drug such as isoproterenol cause a n increase in h eart rate when given
`intravenously but has no ob ervable effect on th e heart when given orally at the
`same dose level. In a ddition , th e bioavailability (a m easure of system ic avai labi l(cid:173)
`ity of a drug) may differ from o ne drug product to a n oth er containing the same
`drug, even for the same route of administration. This differe n ce in drug bioavail(cid:173)
`ability may be manifested by observing th e differe n ce in the therapeutic effec(cid:173)
`tiveness of the drug products. In o th e r wo rds, the nature of the drug molecule,
`the route of delivery, and the formulation o f the dosage form can determine
`whether an admini tered drug i
`therapeutically e ffective, toxic, or has no
`apparent effect at all.
`Biophannaceutics is the science that examines this interrelatio nship of the physi(cid:173)
`cochemical prope rties of the drug, the do age form in which th e drug is given, and
`the route of administration on the rate and exte nt of systemic drug absorption.
`Thus, biopharmaceutics involves factors that influe nce (1) the stabili ty of the drug
`within the drug product, (2) the release of the drug from th e drug product,
`(3) the rate of dissolution/ release of the drug at the absorption site, and (4) the
`systemic absorption of the drug. A general scheme describing this dynamic rela(cid:173)
`tionship is described in Figure 1-1.
`The study of biopharmaceutics is based on fundamental scientific principles and
`experimental methodology. Studies in biopharmaceutics use both in-vitro and in-vivo
`me thods. In-vitro methods are procedures employing test apparatus and equipment
`without involving laboratory animals or humans. In-vivo methods are more complex
`studies involving human subjects or laboratory animals. Some of these methods will
`be discussed in Chapter 14. These methods must be able to assess the impact of the
`physical and chemical properties of the drug, drug stability, and large- cale produc(cid:173)
`tion of the drug and drug product on the biologic performance of the drug.
`Moreover, biopharmaceutics considers the properties of the drug and dosage form
`in a physiologic environment, the drug's intended the rapeutic use, and the route of
`administration .
`
`Dru~ release and
`issolution
`
`Absorption
`
`-
`
`.
`
`Drug in systemic
`circulation
`
`-
`
`.
`
`Drvg in
`tissues
`
`Elimination
`
`,.
`
`Excretion and
`metabolism
`
`I
`I
`I
`I
`
`•
`
`Phormocol:t. or
`
`clinical e
`
`Figure 1-1 . Scheme demonstrating the dynamic relationship between the drug. the drug product.
`and the pharmacologic effect.
`
`MPI EXHIBIT 1045 PAGE 14
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`

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`INTRODUCTION TO HIOPI IARMACEUTICS AND Pl IARMACOKINETICS CHAPTER. I.
`
`3
`
`PHARMA CO KINETICS
`
`Afte1· a drug is released from its d osage form , the drug is a bso r bed in to the sur(cid:173)
`rounding tissue, the bo<ly, o r both . The di stributio n thro ugh and e limina ti on o f
`the drng in the body va ri es for eac h pati e nt but can be c haracte ri zed using math(cid:173)
`ematical rnodels and statistics. Pharrnacohinetics is th e scie nce of the kinetics of
`drug absorption , distributio n , a nd e liminatio n (ie, excre tion a nd me tabo lism ).
`The description of drug distributi o n a nd e li m ination is o fte n termed drug dis(cid:173)
`f>osition. Characterizatio n of drug di spositio n is a n important pre req uisite for de(cid:173)
`te rmination or modification of dosing regim e ns for individuals a nd groups of
`patients.
`The study of pharmacokinetics involves both experimental and theoretical ap(cid:173)
`proach es. The experime ntal aspect of p h armacokinetics involves the d evelo pment
`of biologic ampling techniques, a nalytical m ethods for the measureme nt of drugs
`and metabolites, and p rocedures that facili tate data collectio n and manipulation.
`The theoretical aspect of pharmacokinetics involves th e development of pharma(cid:173)
`cokin etic mode ls that predict drug d isposition afte r drug admin istration. The ap(cid:173)
`plication of statistics is an integral part of pharmacokinetic studies. Statistical me th(cid:173)
`ods are used for pharmacokine tic parame ter estimation and data interpretatio n
`u ltimately for the purpose of designing and predicting optimal dosing regime ns
`for individuals or groups of patients. Statistical methods are applied to pharmaco(cid:173)
`kine tic models to de te rmine data e rror a nd structural mode l deviations. Mathe matics
`and computer techniques form the th eoretical basis of many pharmacokinetic
`meth ods. Classical pharmacokinetics is a study of theoretical mode ls focusing mostly
`on model development and parame te rizatio n .
`
`CLINICAL PHARMACOKINETICS
`
`During the drug d evelopment process, large numbers of patie nts are tested to d e(cid:173)
`termine optimum d osing regimens, which are the n recomme nded by the manu(cid:173)
`facturer to produce the d esired pharmacologic response in the majority of the a n(cid:173)
`ticipate d patie nt population. However, intra- and interindividual variations will
`frequently result in e ithe r a subtherapeutic (drug concentration be low the MEC)
`or toxic response ( drug co ncentrations above the minimum toxic con centration,
`MTC), which may th e n require adjustme nt to the dosing regime n. Clinical phar(cid:173)
`macokinetics is the application of pharmacokinetic me thods to drug therapy.
`Clinical pharmacokinetics involves a multid iscipli nary a pproac h to individually op(cid:173)
`timized dosing strategies based o n the pa tie nt's d isease state and pa tient-specific
`considerations.
`The study of clinical pharrnacokine tics of drugs in disease states re quires input
`from medical and pharmaceutical research . Table l. l is a list of 10 age-adjusted
`rates of death from 10 leading causes of d eath in the United States, 2003. The in(cid:173)
`fluence of many d iseases on drug disposition is not ad equately studied. Age, gen(cid:173)
`der, genetic, an d e thnic diffe re nces can also result in pharmacokine tic differences
`that may affect the outcome of drug therapy. The study of pharmacokinetic dif(cid:173)
`ferences of drugs in vario us po pulation groups is termed population pharmacokinet(cid:173)
`ics (Sheiner and Ludde n, 1992).
`
`MPI EXHIBIT 1045 PAGE 15
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`

`4
`
`CHAPTER 1.
`
`INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS
`
`TABLE 1 . 1 Ratio of Age-Adjusted Death Rates, by Male/Female Ratio from the I 0
`Leading Causes of Death in the USA 2003
`
`DISEASE
`
`RANK
`
`MALE:FEMALE
`
`Disease of heart
`Malignant neoplasms
`Cerebrovascular diseases
`Chronic lower respiration diseases
`Accidents and others*
`Diabetes mellitus
`Pneumonia and influenza
`Alzheimers
`Nephrotis, nephrotic syndrome and nephrosis
`Septicemia
`
`2
`3
`4
`5
`6
`7
`8
`9
`10
`
`* Death due to adverse effects suffered as defined by CDC.
`
`Source: National Vital Statistics Report Vol 52, No. 3. 2003
`
`1.5
`1.5
`4.0
`1.4
`2.2
`1.2
`1.4
`0.8
`1.5
`1.2
`
`Pharmacokinetics is also applied to therapeutic drug rrwnitori.ng (TDM) for very po(cid:173)
`tent drugs such as those with a narrow therapeutic range, in o rder to optimize efficacy
`and to prevent any adverse toxicity. For these drugs, it is necessary to monitor the
`patient, either by monitoring plasma drug concentra tions (eg, theophylline) or by
`monitoring a specific pharmacodynamic e ndpoint such as proth rombin clotting
`time (eg, warfarin). Pharmacokinetic and drug analysis services necessary for safe
`drug monitoring are generally provided by the clinical pharmacokinetic service (CPKS).
`Some drugs frequently monitored are the aminoglycosides and anticonvulsants.
`Other drugs closely monitored are those used in cancer chemotherapy, in order to
`minimize adverse side effects (Rodman and Evans, 1991 ).
`
`PHARMACODYNAMICS
`
`Pharmacodynamics refers to the relationship between the drug concentration at the
`site of action (receptor) and pharmacologic response, including biochemical and
`physiologic effects that influence the interaction of drug with the receptor. The
`interaction of a drug molecule with a receptor causes the initiation of a equence
`of molecular events resulting in a pharmacologic or toxic respon e. Pharmacokinetic(cid:173)
`pharmacodynamic m odels are constructed to rela te plasma drug level to drug
`concentration in the site of action and establish the intensity and time cour e of
`the drug. Pharmacodynamics and pharmacokine tic-pharmacodynamic models are
`discussed more fully in Cha pter 19.
`
`TOXICOKINETICS AND CLINICAL TOXICOLOGY
`
`Toxicokinetics is the application of pharmacokinetic principles to the design, con(cid:173)
`duct, and inte rpre tation of drug safety evalu a tio n studies (Leal et al, 1993) and
`in validating dose-related exposure in a nima ls. Toxicokinetic data aids in the in(cid:173)
`terpretation of toxicologic findings in a nima l and extrapolation of the re ulting
`
`MPI EXHIBIT 1045 PAGE 16
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`INTRODUCTION TO BIOPHARMACEUTICS AND PHAFWACOKINETI CS CHAPTER 1.
`
`5
`
`data to humans. Toxicokinetic studies a re performed in animals during preclini(cid:173)
`cal drug develo pment and may o ntinue arter Lhe drug has been tested in clinical
`trials.
`Cliniml toxirology is the study o r adverse effects of drugs and toxic substances
`(poisons ) in the body. T he pharmacokine tics of a drug in an ove rmedicated (in(cid:173)
`toxicated) patient may be ve1')' diffe re nt from the pharmacokinetics of the same
`drug g ive n in lower therapeutic doses. At very high doses, the drug concentration
`in the bod may saturate e nzymes invo lved in the absorption, biotransformation,
`or a tive re nal secretion mechanisms, the re by changing the pharmacokinetics from
`linear to n o nlinear pharmacokine tics. No nlinear pharmacokine tics is discussed in
`hap ter 9. Drug frequently involved in toxicity cases include acetaminophen, sal(cid:173)
`icylates, morphine, and the tricylic antidepressants (TCAs) . Many of these drugs
`can be a ayed conveniently by fluorescence immunoassay (FIA) kits.
`
`MEASUREMENT OF DRUG CONCENTRATIONS
`
`Becau e drug concentrations are an important element in determining individual
`or population pharmacokine tics, drug concentrations are measured in biologic
`amples, such as milk, saliva, plasma, and urine. Sensitive, accurate, and precise an(cid:173)
`alytical methods are available for the direct measurement of drugs in biologic ma(cid:173)
`trices. Such measurements are generally validated so that accurate information is
`generated for pharmacokinetic and clinical monitoring. In general, chromato(cid:173)
`graphic methods are most frequently e mployed for drug concen tration measu re(cid:173)
`ment, because chromatography separate
`the drug from other related materials
`that may cause assay interfe rence.
`
`Sampling of Biologic Specimens
`Only a few biologic specimens may be obtained safely from the patient to gain in(cid:173)
`formation as to the drug concentration in the body. Invasive methods include sam(cid:173)
`pling blood, spinal fluid, synovial flu id, tissue biopsy, or any biologic material that
`requires parenteral or surgical inte rve ntion in the patient. In contrast, noninvasive
`methods include sampling of urine, saliva, feces, expired air, or any b iologic mate(cid:173)
`rial that can be obtained without pare nte ral or surgical intervention. The mea(cid:173)
`suremen t of drug and metabolite concentration in each of these biologic materi(cid:173)
`als yie lds important information, such as the amount of drug retained in, or
`transported into, that region of the tissue or fluid, the likely pharmacologic or tox(cid:173)
`icologic outcom e of drug dosing, and drug metabolite formation or transport.
`
`Drug Concentrations in Blood, Plasma, or Serum
`
`Measurement of drug concentration (levels) in the blood, serum, or plasma is the
`most direct approach to assessing the pharmacokinetics of the drug in the body.
`Who le blood contains cellular e le m e nts including red blood cells, white blood
`cells, pla te le ts, and various o ther proteins, such as albumin and globulins. In gen(cid:173)
`eral, serum or plasma is most commonly used for drug measurement. To obtain
`serum, whole blood is allowed to clot a nd the serum is collected from the
`
`MPI EXHIBIT 1045 PAGE 17
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`

`

`

`

`

`8
`
`CHAPTER 1. INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS
`
`Drug Concentrations in Urine and Feces
`
`Measurement of drug in urine is an indirect method to ascertain the bioavailability
`of a drug. The rate and extent of drug excreted in th e urine reflects the rate and
`extent of systemic drug absorption. The use of urinary drug excre tion measurements
`to establish various pharmacokinetic parameters is d iscussed in Chapter 15.
`Measurement of drug in feces may reflect drug that has not b een absorbed after
`an o ral dose or may reflect drug that has bee n expe lled by biliary secretion after sys(cid:173)
`temic absorption. Fecal drug excretion is ofte n perform ed in mass balance studies,
`in which the investigato r attempts to account for the e ntire dose given to the patient.
`For a mass balance study, both urine and feces are collected and their drug content
`measured. For certain solid oral dosage forms that do not dissolve in th e gastroin(cid:173)
`testinal tract but slowly leach out drug, fecal collection is performed to recover the
`dosage fonn. The undissolved dosage form is then assayed fur residual drug.
`
`Drug Concentrations in Saliva
`
`Saliva drug concentra tio ns have been reviewed for m a ny drugs for the rape utic drug
`monitoring (Pippenger and Massoud, 1984). Because o n ly free drug diffuses into
`the saliva, saliva drug levels tend to approximate free drug rather than total plasma
`drug concentration . The saliva/ plasma drug con centratio n ra tio is less than 1 for
`many drugs. The saliva/ plasma drug con centration ratio is mostly influenced by
`the pKa of the drug a nd the pH of the saliva. Weak acid drugs and weak base drugs
`with pKa significantly different than pH 7.4 (p lasma pH) generally have better cor(cid:173)
`relatio n to plasma drug levels. The saliva drug co ncentrations taken after equilib(cid:173)
`rium witl1 the plasma drug co ncentratio n gen e rally provide more stable indication
`of drug levels in the body. The use of salivary drug concentrations as a therapeu(cid:173)
`tic indicato r should be used with caution and prefe rably as a secondary indicator.
`
`Forensic Drug Measurements
`
`Forensic science is the application of science to personal injury, murde r, and other
`legal proceedings. Drug measurements in tissues obtained at autopsy or in other
`bodily fluids such as saliva, urine, and blood may be useful if a suspect or victim
`has taken an overdose of a legal medicatio n , has been poiso n ed, or has been us(cid:173)
`ing drugs of abuse such as opiates ( eg, h e roin) , cocaine, o r marijuana. The ap(cid:173)
`pearan ce of social drugs in blood, urine, and saliva drug analysis shows short-term
`drug abuse. These drugs may be eliminated rapidly, making it more difficult to
`prove that the subject has been using drugs of abuse. T he an alysis for drugs of
`abuse in hair samples by very sensitive assay meth ods, such as gas chroma tography
`coupled with mass spectro me try, provides information rega rding past drug expo(cid:173)
`sure. A study by Cone et al (1993) showed that th e hair samples from subjects who
`were known drug abusers contained cocaine and 6-acetylmorphine, a metabolite
`of h eroine (diacetylmorphin e) .
`
`Significance of Measuring Plasma Drug Concentrations
`The intensity of the pharmacologic or toxic effect of a drug is ofte n re lated to the
`concentratio n of th e drug at Lhe recept.or site, usua lly located in the tissue cells.
`
`MPI EXHIBIT 1045 PAGE 20
`
`

`

`INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS CHAPTER 1.
`
`9
`
`e ll arc richly perfused with tissue fluids or plasma,
`Becau e most of the tissu
`mea uring the pla ma drug level is a respon ive method of monitoring the course
`of therapy.
`linicall , indi,~dual varial.ions in the phannacokine tics of d rugs are quite com(cid:173)
`mon. Monitoring the concentral.io n of drugs in the blood or plasma ascertains that
`the calculated dose actually deliver th p lasma level required for therapeutic effect.
`With ome drug , rece