18TH
`
`EDITION
`
`Remington's
`
`ALFONSO I\ GENNAl\O
`Editor, ond Chairman
`of the Editorial Doord
`
`NOVARTIS EXHIBIT 2084
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 11
`
`

`

`Remington's
`Pharmaceutical
`Sciences
`
`18
`
`NOVARTIS EXHIBIT 2084
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 11
`
`

`

`Remington's Pharmaceutical Sciences . .. a rreatise on the rheory
`and practice of the pharmaceutical sciences, with essential
`information about pharmaceutical and medicinal agents: also a guide
`to the professional responsibilities of the pharmacist as the
`drug-information specialisr of the health team ... A textbook
`and reference work for pharmacists, physicians and other
`practitioners of the pharmaceutical and medical sciences.
`
`EDITORS
`
`Alfonso R Gennaro, Chairman
`
`Thomas Medwick
`
`Grafton D Chase
`
`Ara Der Marderosian
`
`Stewart C Harvey
`
`Daniel A Hussar
`
`Edward G Rippie
`
`Joseph B Schwartz
`
`Ewart A Swinyard
`
`Gilbert L Zink
`
`AUTHORS
`
`The 109 chapters of this edition of Remington's Pharmaceutlcol
`Sciences were written by the editors, by members of the
`Editorial Board, and by other authors listed on pages Ix to xi.
`
`Managing Editor
`
`John E Hoover
`
`Edltorlal Assistant
`
`Bonnie Brigham Packer
`
`Director
`
`Allen Misher 1985- 1990
`
`Eighteenth Edition- 1990
`
`Published in the 170th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`NOVARTIS EXHIBIT 2084
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 11
`
`

`

`Table of Contents
`
`Port 1
`
`Orientation
`
`, . . . . . . . .
`
`1 Scope .•... . , ... .. .. ..... , ! . . . . . . . . . .
`, • , • • • • • • • , • , • • • • • • , , •
`2 Evolution of Pharmacy
`3 Ethics .. , .. . . . ..... , , . .... . .. . . , .. ..... .... . , , +
`4 The Practice of Community Pha rmacy .. ••• , , , •.
`5 Opportunities for Pharmacists In the Pha rmaceuti-
`, , • • , • . .• • • , , , , ..• ., ••. , • , , •• •..
`cal Industry
`6 Pha rmacists In Gove rnme nt ••. ,. •.•• • , , , ..••..
`7 Drug Information • • •. , , •• ..••. • . , , , , •• ., ••• , ,
`. , .... , . . ... • • , !
`8 Research
`
`...
`
`. . . . . . . . ,
`
`,
`
`• . . . . . .. . . . . . ..
`
`Port 2
`
`Pharmaceutics
`
`9 Metrology and Calculation • , , , ...••. , , • , •. •. •
`10 Statistics •• , , , , ,, • • • • • • • • , • • • • • • • • • • • • , · • • • •
`11 Computer Science •. •• . , •• •••••••.. , , , .•••..
`12 Calculus , ... , • • • , • • .. , , • • • • • • • • , • • , • • • • • • •
`13 Molecular Structure, Properties and States of
`Matter ...••. ~ .. .... , , .. • .... ., •• , , .. .... ..... , .
`, • .• . .•. •• , ••• . . •••.• , ••
`14 Complex Formation
`. • ,. ..•• • , , ••• ... • . •• , , •• .
`15 Thermodyna mics ,
`16 Solutions a nd Phase Equilibria , •.• • . ••• , , • •• . .
`Ionic Solutions and Electrolytic Equilibria , , •• • • • •
`17
`18 Reaction Kinetics • • •.. •• , , , •.. ..• ••• • . ••.•••
`19 Disperse Sy stems •• .• , • , , ••••.. •• , , •• •• ..•••
`20 Rheology , •• . . .••• , , • ....••• , , , ...••.. , , , ,
`
`Port I
`
`Phormoceutlcol Chemistry
`
`Inorganic Pharmaceutical Che mistry • •• , , , •• . ..
`2 1
`22 Orga nic Pha rmace utica l Che mistry •• •• , , •••• ••
`, , •• , •... . •.• • . , , • , ..•••..
`23 Natural Products
`24 Drug Nomenclature- United States Adopted
`Names ... • , ... .. . .. . . .. i
`25 Structure-Activity Relationship and Drug
`, , , • . . .. •• ... •• • , • , .. . ••... , • • • • • . .
`Design
`
`i • • • , . . . . . . . . . . . , • • • 4
`
`·Port 4
`
`Testing and Analysis
`
`26 Analysis of Medicina ls •• • , , , ••• •..•.•• •• , , . •
`• . . •• • , , ••• .••••••• , • • • • • •
`27 Biological Testing
`28 Clinica l Ana lysis ••... • , , ••••. . •••. , , • • • • . • •
`29 Chromatogra phy •• , • , •• ••••..•• •• , , • • • • • • • •
`.
`Instrume nta l Methods of Ana lysis • , , , , • . . . • •
`30
`31 Dissolution •••• • , , , , • • ••• • ••••• • •• • ••••• , • ,
`
`3
`8
`20
`28
`
`33
`38
`49
`60
`
`69
`104
`138
`145
`
`158
`182
`197
`207
`228
`247
`257
`3 10
`
`329
`356
`380
`
`4 12
`
`422
`
`435
`484
`495
`529
`555
`589
`
`Port 5
`
`Radioisotopes In Pharmacy ond Medicine
`
`32 Funda me ntals of Radioisotopes •• ••••• • , • . ••••
`33 Medical Applications of Radioisotopes • . .. ••• , •
`
`605
`624
`
`Port 6
`
`Pharmaceutical and Medicinal Agents
`
`34 Diseases: Manifestations and Patho.
`physiology , , •• , , ••.• • • •• • , ••• •• , • , • • ••• , , ,
`35 Drug Absorption, Action and Disposition ••• , . , , •
`36 Basic Pha rmacokinetlcs , • , , , •• , • •••••• • • , , •••
`37 Clinical Pharmacokinetics , ••• ..•••.. •••• , • •• .
`38 Topical Drugs • • ,, •• •••• , • •• •• • •••• , •• ,, ••• • ••
`39 Gastrointestina l Drugs , , , •• •. ...••• • , ••• • • . ..
`40 Blood, Fluids, Electrolytes a nd He matologic
`...... .. ....... ~ ~ . . ....... ., .!! • • • • • • • • • • • •
`Drugs
`4 1 Cardiovascula r Drugs •••••• , , , • ••• ••• • , , , , ••
`. .•• •• , , • , . . •• . . . •• , , , •••.
`42 Respiratory Drugs
`43 Sympathomime tic Drugs , • • •• . • • ••• ••• , ••.•••
`
`,
`
`655
`697
`725
`746
`757
`774
`
`800
`83 1
`860
`870
`
`.. .. •
`
`889
`
`44 Cholinomimetic Drugs .•• •••• ..•....• , , , , , ••.
`45 Adre ne rg ic a nd Adrenergic Ne uron Blocking
`898
`• , • , . .. .. ....... , ........ , r •• , • • • • • • •
`Drugs
`907
`46 A ntlmuscarinic a nd A ntispasmodic Drugs • • • • • • •
`9 16
`47 Skeleta l M uscle Relaxants ..• •••• ..• •••. , , • , .
`929
`• , , ••• ••. • , , , •• •••••••• •• , • • •
`48 Diuretic Drugs
`943
`49 Ute rine and Antimigraine Drugs ••.• • , ••• , • . . .
`948
`50 Hormones •• , , ••• ..• •• , , , • • . • • • • • • • . • • • • . • .
`1002
`5 1 Vita mins and Other Nutrients ... ••. , , ••.. .• •• ,
`1035
`, , •• ••• • , • , ••• .• ••• , , , ••••• ••• . , ,
`52 Enzymes
`1039
`53 Gene ral A nesthetics • •• .• •••.•• , .••....• • , , ,
`1048
`54 Local A nesth etics , ••• ••• • •• , •.•• •.•••• •• , , • .
`1057
`55 Sedatives a nd Hypnotics •• , , •.• ••••.. •• , • • . . •
`1072
`56 A ntleplleptics •••• • • • •• , • •• •• . •••••• , , • • . • •
`1082
`57 Psych opha rmacologic Agents ..• ••. , • , • . • • • • •
`1097
`58 A na lgesics a nd Antlp yretics •• • •••• , , •• • . • •• • ,
`11 23
`59 Hista mine a nd Antihista mines ••. , •••• ..••.•. ,
`1132
`60 Centra l Nervous Sy stem Stimula nts , • .•.. • , , • , ,
`1138
`6 1 Antineoplastic and lmmunosuppressive Drugs . . .
`1163
`62 A ntimicrobia l Drugs •••••• , •••• , ••. .• ••• , • , • •
`1242
`63 Parasiticldes • • • • • . . . • • . . • • • • • • • . . . • • • • • • • . .
`1249
`64 Pesticides . •••• , •• •.•••• •• , • • • • . . • • • • • • • • . .
`1272
`65 Diagnostic Drugs • . ••.•• • , , .•••••• • , . • • • . . . .
`1286
`66 Pharmaceutica l Necessities ••••••• , • • , . • • • • . .
`1330
`67 Adverse Drug Reactions • ..•••..•• , , • • . . . • • • •
`68 Pharmacogenetics • , , , ,. •. . • •.. , • , •••••.••. , .• , 1344
`1349
`69 Pharmacological Aspects of Drug Abuse . . . . • . . .
`1365
`• , , ••• •••••• , , , • • . .
`Introduction of New Drugs
`70
`
`Port 7
`
`Diologicol Products
`
`71 Principles of Immunolog y ••• .. •••..•• , ..• ,, •..
`Im munizing Agents a nd Diagnostic Skin
`72
`.. , ....... ... , • . , •.. ... .••• ~
`Antigens ...... , ..... ,.
`73 A lle rgenic Extracts , , •• ,, ... •. , , •• .••• ••• , , , • •
`74 Biotechnology a nd Drugs .. , , ••••• .. ••••••• ••
`
`1379
`
`1389
`1405
`14 16
`
`Port 8
`
`Phormoceutlcol Preparations and Their
`Manufacture
`
`75 Preformulation .. , ••• •. • .. ••• , , •••• . .•• • •• , •
`, , , •.
`76 Bioavailability and Bioequiva le ncy Testing
`Separation .. • , ...... .. , , , . .... .... . ...... , ... ~
`77
`, , •••...••. , •• • .• • ••.• • •••••.•.
`Steriliza tion
`78
`Tonicity, Osmoticity , Osmola lity a nd Osmolarity .
`79
`Plastic Packaging Materia ls • . . •• •• , ••...•••..
`80
`Stability of Pharmaceutical Products •• .•• • , ••. , •
`8 1
`Quality Ass ura nce and Control •••.. .... •••• , ,
`82
`Solutions, Emulsions, Suspensions a nd
`83
`, .. , , .... . . .... , .... ... . .. ... , , , .. .
`Extractives
`84 Parenteral Preparations • , •• .•••...• • , , , , ••••
`Intravenous Adm ix tures , ••• ..•••. , • , , ••••...
`85
`86 Ophthalmic Prepa rations • •.. ••• , , •• •••• • .•••
`87 Medicated Applications .•• . • . •• , , , ••..• , • .. ,
`88 Powders ••• • .. , , • , •••• . • •• • , , •• , , ..... .. . , ••
`Oral Solid Dosage Forms ... •• , , • ••.•• ••. • , •••
`89
`Coating of Pharmaceutical Dosage Forms •• •••••
`90
`Sustained-Release Drug Delive ry Syste ms ••..••
`9 1
`Aerosols , • , .. . . .... , , .. ........ ,. ~ • .!!
`92
`
`•
`
`• • • • • • ,, , •
`
`,
`
`1435
`145 1
`1459
`1470
`148 1
`1499
`1504
`15 13
`
`15 19
`1545
`1570
`1581
`1596
`1615
`1633
`1666
`1676
`1694
`
`Port 9
`
`Pharmaceutical Practice
`
`93 Am bulatory Patient Care .•..• ••• ••• • .••• , •.•
`Institutional Patient Care .••. , •••• . ••. .. , ••• •
`94
`, . , ••• •..• ••••• , • •••
`95 Long-Term Care Faci lities
`. ••• , , •••. ..•
`96 The Pharmacist and Public Health
`
`17 15
`1737
`1758
`1773
`
`xv
`
`NOVARTIS EXHIBIT 2084
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 11
`
`

`

`97 The Patient: Behavioral Determinants ••••• , , , •• 1788
`1796
`99 Drug Education ........................ ' ... 1803
`98 Patient Communication
`
`(cid:127)
`
`(cid:127)
`
`(cid:127)
`
`•
`
`(cid:127)
`
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`
`t
`
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`
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`
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`
`(cid:127)
`
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`
`(cid:127)
`
`a.
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`
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`~ (cid:127)
`
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`
`t
`
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`(cid:127)
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`(cid:127)
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`(cid:127)
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`
`(cid:127)
`
`(cid:127)
`
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`
`• • • (cid:127)
`
`(cid:127)
`
`(cid:127)
`
`(cid:127)
`
`~ 1
`
`(cid:127)
`
`(cid:127)
`
`(cid:127)
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`1905
`1914
`
`106 Poison Control
`107 Laws Governing Pharmacy
`108 Community Pharmacy Economics and
`Management
`109 Dental Services •
`
`(cid:127) • N
`
`(cid:127)
`
`(cid:127)
`
`I
`
`(cid:127)
`
`(cid:127)
`
`1940
`1957
`
`(cid:127)
`
`(cid:127)
`
`p
`
`•
`
`I
`
`• ~ 1
`
`t,
`
`'
`
`(cid:127)
`
`It
`
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`(cid:127)
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`(cid:127)
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`(cid:127)
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`
`'I!
`
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`
`(cid:127)
`
`(cid:127)
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`(cid:127)
`
`• •
`
`(cid:127)
`
`I
`
`t
`
`IOI
`
`(cid:127)
`
`(cid:127)
`
`(cid:127)
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`(cid:127)
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`(cid:127)
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`
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`
`(cid:127)
`
`(cid:127)
`
`(cid:127)
`
`, ,
`
`1813
`100 Patient Compliance
`1828
`101 The Prescription (cid:127)
`1842
`102 Drug Interactions (cid:127)
`1859
`103 Clinical Drug Literature ••••• •••• +t- ••• • ••••t foll
`104 Health Accessories ... .... ............... . ,. 1864
`1895
`105 Surgical Supplies I
`
`•
`
`(cid:127)
`
`(cid:127)
`
`(cid:127)
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`(cid:127)
`
`I
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`
`fl
`
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`(cid:127)
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`
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`
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`
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`
`•
`
`(cid:127)
`
`Index
`
`Alphabetic Index
`
`, • • • • • • • • ,
`
`.
`
`... . . . . . . . , • • • t • •
`
`1967
`
`xvi
`
`NOVARTIS EXHIBIT 2084
`Breckenridge v. Novartis, IPR 2017-01592
`Page 5 of 11
`
`

`

`CHAPTER 36
`
`Dasie Pharmacokinetics
`
`Stewart C Horv•y. PhD
`Professor of Pharmacology
`
`and C Dean Withrow, PhD
`Associate Professor of Pharmacology
`School of Medicine, University of Utah
`Salt Lake City, UT 64132
`
`Pharmacokinetics is the discipline which is concerned
`with the rates of movement of a drug or its metabolites into
`the body, among its many compartments, out of the body
`and also which attempts to evaluate the rates of biotransfor(cid:173)
`mations of the drug and its metabolites. As in chemistry, it
`involves primarily following the rate of change in concentra(cid:173)
`tion in the appropriate compartment(s), most often in the
`extracellular fluid (plasma) and/or urine. However, phar-
`
`macokinetics is by no means limited to observations of con(cid:173)
`centration; rates of movement of a drug can be followed by
`isotopes or other means. The application of pharmacoki(cid:173)
`netics to drug formulation and treatment regimens also is
`within the scope of this title. The applications to treatment
`regimens and other clinical uses of pharmacokinetics are
`treated in Chapter 37, Principles of Clinical Pharmacoki(cid:173)
`netics.
`
`Orders of Processes
`dioactive decay, diffusion into infinite space, some exen(cid:173)
`The order of any process is determined by the probability
`tropic SN1 chemical decompositions and certain enzymatic
`that the appropriate unit events will occur in a given popula(cid:173)
`reactions. However, in a confining space, diffusion and
`tion within a given time. Processes may be zero-order, first(cid:173)
`many chemical reactions reach an equilibrium state in which
`order, second-order, etc, depending upon the numbet of
`C approaches a finite asymptote as t approaches infinity.
`variables that determine the probability. In pharmacoki(cid:173)
`Figure 36-1 illustrates a simple situation in which the asymp(cid:173)
`netics, only zero-order and first-order. processes are impor(cid:173)
`tote is necessarily finite. To satisfy the conditions of this
`tant, the latter being of overwhelming significance; conse(cid:173)
`quently, only the kinetics of these two . processes will be
`treated in· this chapter.
`
`20
`
`Comportment I
`Volume = v
`
`/
`
`16
`
`14
`
`18 I
`\
`\
`\
`\
`\
`\
`\
`fl
`I
`I
`I
`
`4
`
`2
`
`Volume=4V
`
`First-Order Processes
`When activity is random within a population of a single
`species, the probability that a given event will occur is di(cid:173)
`rectly proportional to the size of the population. For exam(cid:173)
`ple, the probability that some atom in a population of radio(cid:173)
`nuclides will disintegrate in any instant is directly propor(cid:173)
`tional to the number of radionuclide atoms in the
`population. Similarly, the number of molecules of drug that
`diffuse across a given boundary (eg, the vascular endotheli(cid:173)
`um) per unit time will be proportional directly to the num(cid:173)
`ber of molecules near the boundary, which, in turn, is pro(cid:173)
`portional to the concentration. This is the basis of Fick's
`Law of Diffusion (page 208). Any process in which the rate
`of change in a population is directly proportional to the
`In such a
`population is known as a first-order process.
`process, the time-dependent change in concentration is de(cid:173)
`fined by the equation
`(1)
`[units of wt • vol- 1 or molar, etc]
`where C is the concentration at time t, Co is the initial
`concentration (time zero), tis time, e is the natural (Naper(cid:173)
`ian) log base and k is a proportionality constant known as
`the rate constant. (For a derivation of Eq 1, see page 247.)
`In a diffusion process, the magnitude of k is determined by
`the temperature, mobility, permeability and other factors.
`The numerical value of k also will depend upon the time
`units (min vs hr, etc) chosen.
`Eq 1 predicts that as t approaches infinity, C approaches
`zero, which would be true for irreversible processes like ra-
`
`725
`
`N
`4a.
`3E 0
`u
`2 .s
`I u C 08
`
`7
`
`0
`
`2
`
`3
`
`5
`
`6
`
`4
`Time
`Idealized diffusion kinetics of a hypothetical drug that
`Fig 36-1.
`equilibrates between two compartments. Transfer Is from compart(cid:173)
`ment 1 Into compartment 2. The equilibrium concentration is ¼ of
`that initially in compartment 1, because the final volume of distribu(cid:173)
`tion is 5 times that of compartment 1.
`
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`

`726 CHAPTER 36
`
`closed syst.em, (Co - C,) must lie substituted for Co in 1£4 I.
`C, being the equilibrium concentration.
`In Eq l, the algebraic sign of k is usually negative, which
`ind icates a diminishing concentration with time. However,
`in Fig 8G- l the conoent.ration in compartment 2 rises loga(cid:173)
`rithmically with time; nevertheless, h is negative, since the
`rate diminishes exponentially wit,h time, The equation for
`the logarithmically rising concentration in compartment 2
`will take the form of Eq 5 (page 727}, in which C, would be
`used in lieu of c;.
`Eq I can be written in the Jog form,
`log('= log Co - 0,434kt
`
`[no units]
`
`(2)
`
`The coefficient 0.434 results from the conversion of the nat(cid:173)
`ural log base, e, to log base 10 (0.434 = l/2.303), The equa(cid:173)
`tion determines that e plot of log C against twill be rectilin(cid:173)
`ear (bottom oJ Fig 36- l) with a slope of -0.434k and an
`orclinat.e-intercept of Co. For pharmacokinetics, this is a
`useful t.ype of plot, because, in the straight-line form, back
`extrapolation to estimate Co is easier and more accurate l,han
`Crom a curve, and k can also be determined graphically.
`Rate Constants and Hulf -Life--Since first-order pro(cid:173)
`cesses are characterized by exponential or logarilhmic kinet(cid:173)
`ics, it follows that a constant fraction of the present or
`instantaneous population (eg, concentration) changes per
`unit Lime, that fraction heing equal to 0.434h; k has the units
`oft-•, Another way of expressing the rate of change is that
`of half-time (or especially half-life, if the population is de(cid:173)
`creasing), with the uotation tvi- The half-time is the t:ime
`
`that it takes the population to decrnase (or increase) by 50%
`of the total p,Jssible change. By setting C e((ual to 11;c0 io
`either Eqs l or 2 and solving for t (which is l 112 under these
`constraints),
`
`_ 0.698
`t
`' l/2- - k -
`
`[units of time]
`
`(3)
`
`Zero-Order Processes
`
`When an enzyme or transport system is saturated, the
`activity cannot be increased further by increases in the con(cid:173)
`centration of substrate. Consequently, the rate remains
`constant so long as the concentration ofsobstrate is in exceS11
`of the saturating concentration. ln this situation, the rate is
`independent of the concentration. The kinetics are de(cid:173)
`scribed as being of zeru-order, and it is customary to speak or
`the process as being a zero-order process. The equation
`describing zero-order kinetics is
`C = C0 - kt
`lcouc vol 1]
`(4)
`where k has the units of amount/unit t ime. A plot of C
`against ton Cartesian cooYdinates will yield a straight line; a
`p lot of log C against twill yield a curved line. As the process
`continues, the concentration eventually will fall to subs11tu
`ration levels, and the kinetics will change, usually to first(cid:173)
`order kinetics, so that it is more appropriate to speak of the
`initial kinetics and not the process as being zern-01·der .
`
`. Pharmacokinetic Models
`The plasma, cerehrospinal fluic.l, interst.itial space, glan(cid:173)
`gram, such an open one-compattment model is depicted in
`Fig 36-2. In t,he diagram, the compartment represen1.s tho
`dular or renal tubular lumina, gall bladder, etc and each cell
`are all compartments which a drug may or may not enter or
`entire hotly (ell:duding the lumina of the gastrointest,inal
`leave with different rate constants, In addit.ion, binding to
`tract, urinary tract, pulmonary alveoli, etc, which communi(cid:173)
`cate with the open environment). The term, Vd is the vol(cid:173)
`protein or other sequestration also is governed by character(cid:173)
`ume of distribution (see page 727), However, Vd is uot
`istic rate processes. Conseq1.1ently, it might be expected
`necessarily that of the body or even total body water: as
`that the kinetics of absorption, distribution and elimination
`noted on page 728, the volume of distribution, Vd, is a fictive
`would be very complex and J>erhaps beyond analysis and
`one considered to he equal to {D/Cp (where/ is the fraction
`mathematical description. Fortunately, the rates of distri(cid:173)
`absorbed, D is the dose and Cp is the plasma concentration)
`bution among the various tissues and myriad cells generally
`in which it hypothetically is assumed that the concentration
`are not dispersed greatly, and most such processes are first(cid:173)
`is.the same t hroughout the volume end is equal to Lhe plas(cid:173)
`order. Thus, the ki11etics behave as though t he drug were
`ma concentration. In reality, concentration is not homoge·
`being distributed among one, two or, at the most, a few
`compartments, and they are amenable to mathematical
`neous t hroughout, but this cannot be determined from rJP
`alone (which simply averages al! inputs and outputs); as loug
`modeling. Like the vol\une of distribution (plij(e 727), a
`as distribution equilibrium is achieved rapidly, the kmetics
`pharmacokinetic compartment is fictive or virtual and may
`be difficult to define in precise anatomical terms, There•
`as perceived through blood or urine coucentratlons are the
`same whether distribution is homogeneous or beterogene•
`fore, a compartment is defined mainly by its pharmacokinet(cid:173)
`ic pa:rarneter.s.
`ous.
`
`Open One-Compartment Model
`
`Volume• Vd
`
`Tu tl1is model, the body is assumed to behave as though it
`were a si11gle compartment, that is, as t hough t here were no
`barriers to movement, of a drug within the Lota! body space
`aL1d as though the final e4uilibrium disl,ribution is attained
`instantaneously,
`ln practice, the model adequately de(cid:173)
`scribes the pharmacoki11etic behavior of a drug if the [inal
`equilibrium distribution is attained rapidly in comparison to
`the rates of absorption and elimination. The term open
`indicates that input and output (frum any and all routes of
`administration and elimination, respectively) 11re unidirec(cid:173)
`tional and that the one compartment (ie, body) is not within
`a confined space and hence does not come int,o chemical
`equilibrium with its external environment. ln simple dia-
`
`ko
`O -1-N-PU_T _ _,, • - , De
`cl
`(obsorpllon)
`
`OUTPUT
`lelominotlon)
`
`Fig 36-2. The open one-compartment pharmacoklnetlc model. An
`amount of drug, 0 8, Is absorbed from the administered dose, 0, with 8
`rate constant of k. lnlo a compartment with volume Vdarid Is dlstrlbut·
`ed Instantaneously to reach a plasma concentration Cp, V0 Is ob•
`talned by dividing 0 8 by Cp- 0 8 : dose O times f, the fractioO
`absorbed. Drug Is eliminated tram the compartment with a rate
`constant k,,, 0 0 Is the amount excreted Into urine, feces, expired air,
`sweat, milk, etc; Om ls the amount of drug metabolized.
`
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`

`BASIC PHARMACOKINETIGS
`
`727
`
`,. I 0 s .. C.
`
`.i
`E
`.....
`~ 0,5
`€ .. .D
`0 c
`" ~
`"" =t. 0
`
`..
`
`Iu order t o derive formulae to dei,ni be time-relaLed
`<'hanges in C,,. it is cunvenieni to conRider absorptiol) a11r!
`elimint1tion separately, as t.hollgh each were occurring in the
`absence vf the other, then w add them algebraically to d eter(cid:173)
`mine the total it1tegl'a] kinetics.
`Absorption- If a drug is admi11istered in1,ravenously in a
`single, rapid inject.ion, absorp~ion is bypassed. The time for
`such injections is usually s•> short. compared to other phar(cid:173)
`macokinet,ic processes that it. is cuswmnry to consider the
`peak plasma concentratiun and equilibrium distribution \,\,1
`occur instant.aneously in one-compartment.systems. This is
`depicted in panel A of Fig 36-3. In the model for the figure,
`there is no elimination and Cp remains constant onC'e injec(cid:173)
`t.ion is accomvlisbed, With canst.ant intravenous infusion
`(panel BJ, Cµ rises rectilinearly so long as infusion continues
`at a conatant rate. With other routes of administration,
`absorption usually manifests first-order kinetics, since most
`drugs are a!Jsurbed by simple diffusion. Thus, the drug
`disappears exponentially from the site uf administratiw1 (as
`from cumpartment. 1 in Fig 36-L). The equation for the
`concenLration of a drug in the plasma after a single extravas(cid:173)
`cular dose of a drug, assuming no elimination takes place, is
`
`Cp=c;-cpe- k,I
`!units: wt•voJ- 1,etc]
`(5)
`where C,, is the concentration at time I, Cw is the final
`concentration at "infinite" Lime and k., is the absorption rate
`constant (units; time-1 ). Absorption is characterized by a
`half-time equal to 0.693/k0 • Bimolecular absorption pro(cid:173)
`cesses, such as facilitated diffusion or nctive transport., also
`uften show first-order kinetics, especially at drug concent.ra(cid:173)
`tions well below those at which the carrier system will be(cid:173)
`come saturated, At saturation, the kinetics become zero(cid:173)
`urder, Even the rate of dissolution of a drug app1•oximates a
`first-order process, provided t.h11t Lhe drug is soluble readily
`and diffuses rapidly, If the solubility and diffusibility are
`low, it will approximate a 1.ero-order process so long M there
`is saturation around the solid phase. Some sustained-re(cid:173)
`lease dosage forms are designed to release drugs at a <:on(cid:173)
`stant rate (zero-order) over long periods of time.
`Absorption by the oral route rarely conforms t.o simple
`first-order kinetics. A drug is absorbed at different rates
`from the stomach ntid the three segments of the intest,ine,
`i,attly simultaneously and µartly sequentially. Absorption
`from the stomach usually is quite s low compared l.o t hal,
`from the small intestine, and it is sometimes so slow that. a
`significant amount of drug appears fn the blood only aft.er
`the stomach contents are emptied. Thus, there may he a lag
`between the time of drug administration and f he appearance
`of drug in the blood. '!'hat is, the curve describing the time(cid:173)
`dependent rise in Cp does not pass through the origin. An
`example of lag in the absorption of pentobarbital is shown in
`Fig 36-4. Enteric-coated or other delayed-release dosage
`forms also cause lag. The mathematical formulation of lag
`
`Ropid Intravenous
`
`Constant jnfro-
`
`Eitrovenous
`
`Ii our$
`HO\lrs
`iiou1'
`Fig 36-3. Tlme-conoentratlon curves for Injection (A), Infusion (6)
`and extravenous (CJ administration of drug In the one-compartment
`model, The volume of the compartment Is 100 L (Vd = 100 L): the
`amount ot drug administered In each Instance Is 1000 mg. Drug
`elimination has been set to zero, so that the time-concentration curve
`for each model of admlnlsl! atlon can be examined without the compli(cid:173)
`cation of simultaneous elimination (courtesy, Bigger, 1 adapted).
`
`( r: .. :·~ . " .1:~~~::~J c:··, .. : .. : ..
`
`.. _ ........ _ _.__.._
`
`5 .0
`
`6 ,0
`
`IO 2,0 3.0 4 ,0
`Hours
`Fig 36-4. The time course of pentobarbital In the blood of a tasting
`human subject following the oral adm!nlsl!ation or 50 mg. The figure
`shows a tag-time of about 20 min, approximately the emptying time of
`the lasting stomach (courtesy, Dlttert2).
`
`will be deferred to the next section in connection with Eq 28.
`Factors affecting absorption ere enumerated on page 713.
`Some changes in gastrointestinal conditions during the
`course of absorption are part of diurnal rhythms or are
`caused by the drug itself, which make it impossible Lo estab(cid:173)
`lish a steady basal state for description; others may result
`from emotionality, ingestion of foodstuffs, water, other
`drugs, etc, aud can he cont.rolled adequately for ~cientlfic
`purposes but may vary greatly in practical circumstances.
`Absorption by other routes is also subject to variability,
`Some drugs that are compleLely absorbed in normal patients
`may not be absorbed in persons with abnormal gastrointesti·
`nal function, as t he result of genetic, pathological or surgical
`factors. Many drugs are not absorbed completely even
`when gastrointestinal function is optimal. Absorption can
`be limited by the physical state of the drug and by other
`substances in the dosage form. The amount of drug ab•
`sorbed into t.he body (DH) is related to the dose M foUows:
`D,1 = f D
`(units: wt]
`(6)
`where DIJ is the amount absorbed (drug in the body),/ is the
`traction abs<>rbed and V is the dose administered. T he
`,property of a drug to be absorbed from its dosage form is
`known as bioavailability, and/ is the bioavailability factnr.
`'!'be biuavailability factor often is determined by compari(cid:173)
`son of the area under the concentration curve (AUC) of a
`given dose of drug given orally with that of the same dose
`given intravenously (see page 736).
`Distribution- In the open one-compart.roent model, the
`body is treated as t h.ough it were a single compartment in
`which the absorbed clrug is mixed inst.antaneously and ho(cid:173)
`mogeneously, Clearly, the assumption of instantaneous
`e11ui_librium establishes only an ideal mathematict1l bound(cid:173)
`ary condition to facilitate pharmacokinetic calculations. At
`best, no drug could be equilibrated in less than one circula(cid:173)
`tion time, and no drug has been shown to distribute so
`rapidly. However, for practical purposes, a distdbution
`time of a few minutes is negligible compared to absorption
`and elimination times. Only water-soluble drugs of small
`molecular size which are confined completely to the exira(cid:173)
`c~ellular space equilibrate rapidly enough t.o meet the re(cid:173)
`quirements of the ideal one-compartment model, but, for
`clinical purposes, the one-compartment model is adequate
`to describe the pharmacoki Detics of a large number l)f drugs.
`Volume or Distribution and Distribution Coeffi(cid:173)
`cient-The hypothetical volume within which a drug is dis•
`tributed is !mown as the uolume of di.~tribution, Va, l t may
`be calculated by dividing the amount of drug in the body,
`DR, by the plasma concentration, Cp, where. Cp is t.he concen(cid:173)
`tration iu plasma. lt is important t.u note that C Pis usually
`the total coocentraLion of unbound pins bound cl rug. Under
`real condiLions, On and C,, vary with time, and computation
`
`NOVARTIS EXHIBIT 2084
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`

`728 CHAPTER 36
`
`mUBt be made in such a way as to eliroinate the tirne variable.
`One such way is to extrapolate C,, to zero time (eg see Figs
`M-6 and 36-8), in which case
`'
`
`(7)
`where D is the dose administered, f is the hioavailabili~
`factor (traction that. reaches the systemic circulation) and c<~
`is the plasma concentration at zero time, determined b;
`
`Lrrapolation. When the drug is given intraveuously, Du=
`
`Of 1•11uTs_e, V~wiH var_ywitb body weight, so that ii. needs to
`be normaltzed in a way that allows comparisons among indi(cid:173)
`viduals of different body weights. Such a normalized Vd is
`the distribution coefficient,• t:,.', calculated by the equation
`fl'= Va!RW
`(8)
`where BW is body weight. Units are usually rnL/g or L/kg,
`an? c11re must, be taken to employ the appropriate unitA of
`weight, concentration and volume in Eqs 7 and 8. The
`notation t:l is a more serviceable parameter than VJ and is
`t,he form of Vd usually found in tables of pharmacokinet;io
`rlata, usually under the heading, "\folume of Distribution,"
`rather then t:,.1•
`. Alt.hough Vd and fl' are derived as though the concentra(cid:173)
`tion was equal to Cp throughout the volume, concentration
`is, in fact, almost never homogeneous, and consequently Vd
`and fl' are only imaginary (fictive, virtual) volumes. Factors
`t,hat make for nonhomogeneous distribution are: binding to
`prote.ins, dissolution into body lipids, pH part.ition, active
`transport, electrochemical and Donnan distributions, etc.
`Even if Cp (free) rather than Gp (total) is used to calculate
`Vd, Vd would not represen~ a real space, because of these
`manifold factors that cause uneven distribution. Conse-.
`quently, the prindpal ut.ility of VJ or fl' is not so much in
`permitting an estimation of where the drug is distributed
`but rather as a measure of the reservoir from which a drug is
`being delivered and/or cleared (see page 729 and 'rable n,
`p~ge 731). ~o':"ever, with appropriate considerations, V d or
`fl also may indicate the general ability of a drug to penetrate
`membranes, dissolve in fat or bind exrensively to extravas(cid:173)
`cular macromolecules.
`Highly polar, poorly pen etrant drugs I.end to be confined
`mostly to the extracellular space; if these drugs are little
`bound to plasma proteins, they will have /l's of about 0.3
`mL/g, less if there is significant binding to plasma proteins.
`T~e lower limit to Ii' is about0.04 mL/g, which approximate(cid:173)
`ly ts equal to the plasma volume. Drugs that are distributed
`throughout hotly water and are not bound or concentrated
`h~v~ A's of approximately 0.7 mL/g, the A' of body water.
`Llp1d-soluble drugs that are bound negligibly to plasma pro(cid:173)
`tein have 1'1's that range usually from about Q.7 to 3----4 mL/g,
`depending upon weter-lipid distribution coefficien