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`215T EDITION
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`Remington
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`The Science and Practice
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`of Pharmacy
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`MYLAN INC. EXHIBIT NO. 1035 Page 1/
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`MYLAN INC. EXHIBIT NO. 1035 Page 1
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`Printed in the United States of America
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`Entered according to Act of Congress, in the year 1885 by Joseph P Remington, in the Office of the Librarian of Congress, at
`Washington DC
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`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
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`MYLAN INC. EXHIBIT NO. 1035 Page 2
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`12345678910
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`MYLAN INC. EXHIBIT NO. 1035 Page 2
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`

`

`, A treatise on the theory
`_
`Remington: The Science and Practice of Pharmacy .
`and practice of the pharmaceuticai sciences, with essentiai
`information about pharmaceutical and medicinai agents, aiso, a
`guide to the professionai responsibitities of the pharmacist as the
`drug information speciaiist of the heaith team .
`.
`. A textbook and
`reference work for pharmacists, physicians, and other practitioners of
`the pharmaceuticai and medicai sciences.
`
`EDITORIAL BOARD
`
`Paul Beringer
`
`Pardeep K. Gupta
`
`Ara DerMarderosian
`
`John E. Hoover
`
`Linda Feiton
`
`Nicholas (3. Popovick
`
`Steven Gelone
`
`William J. Reiliy, Jr
`
`Alfonso R. Gennaro
`
`Randy Hendrickson, Chair
`
`AUTHORS
`
`The 133 chapters of this edition of Remington were written by
`
`the editors, by members of the Editorial Board, and by the au-
`
`thors listed on pages xi to xv.
`
`Director
`
`Philip P Gerbino 1995-2005
`
`Twenty-first Edition—2005
`
`Published in the 185th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`MYLAN INC. EXHIBIT NO. 1035 Page 3
`
`MYLAN INC. EXHIBIT NO. 1035 Page 3
`
`

`

`Drug Absorption. Action. and Disposition
`
`Michael R Franklin, PhD
`
`Donald N Franz, PhD
`
`CHAPTER 57
`
`6i
`
`'5:
`
`
`
`Although drugs differ widely in their pharniacodynamic effects
`and clinical applications: in penetration. absorption. and usual
`route ofadministratimi: in distribution among the body tissues;
`and in disposition: and mode of termination of action= there are
`certain general principles that help explain these differences.
`These principles have both pliarmaceutic and therapeutic im-
`plications. They facilitate an understanding ol‘ hot-11 the fea—
`tures that are common to a class of drugs and the differences
`among the members oft-hot class.
`For a drug: to act it must be absorbed. transported to the ap-
`propriate tissue or organ. penetrate tn the responding cell sur-
`
`face or subcellular structure. and elicit. a response or alter on;
`going processes. The drug may be. distributed simultaneously or
`sequentially to a number of tissues. bound or stored. metabo-
`lized to inactive or active products, or excreted. The history ofa
`drug in the body is summarized in Figure 57—1. Each ol'the pro
`cesses or events depicted relates importantly to therapeutic
`and toxic effects of a drug and to the mode of administration.
`and drug design must take each into account. Since the effect
`elicited by a drug is its rots-on d’étr'e. (ling action, and effect are
`discussed lirst in the text that follows. even though they are
`preceded by other events.
`
`The word drug” imposes an action—effect context within which
`the properties of a substance are described. The description of
`necessity must include the pertinent properties ofthe recipient
`ol'tlie drug. Thus. when a drug is defined as an analgesic. it is
`implied that the recipient reacts to a noxious stimulus in a cer—
`tain way. called pain. rStudies indicate that pain is not simply
`the piv'cepfion of a certain kind of stimulus but rather. a F'C‘GC'
`tion to the perception of a variety of kinds of stimuli or stimu—
`lus patterns. 1 Both because the. pertinent properties are locked
`into the complex and somewhat imprecise biological context.
`and because the types ofpossiblo response are many. descrip-
`tions of the properties of drugs tend to emphasize the qualita-
`tive features of the efl'ects they elicit. Thus. a drug may be de-
`scribed as having analgesic. vasodepressor. convulsant.
`antibacterial. etc. properties. The specific effect {or use: cate—
`gories into which the many drugs may be placed are the subject
`of Chapters 64 through 89 and are not elaborated upon in this
`chapter. However. the description ofa drug does not end with
`the enumeration of the responses it may elicit. There are cer—
`tain intrinsic properties of the drug-recipient system that can
`be described in quantitative terms. and that are essential to the
`full description ol'the drug and to the validation of the drug for
`specific uses. Under Definitions and Cont-epis- below. certain
`general terms are defined in qualitative. language; under Dose-
`Ef'fi‘ct Rt'i’orionmliips the foundation is laid for an appreciation
`of some ol'thc quantitative aspects of pharmacodynamics.
`
`DEFINITIONS AND CONCEPTS
`
`In the field of pharmacology. the vocabulary that. is unique to
`the discipline is relatively small. and the general vocabulary is
`that of the biological sciences and chemistry. Nevertheless,
`there are a l‘ew definitions that are important to the proper un—
`
`derstanding of pharmacology. It is necessary to differentiate
`among action. effect, selectivity, dose. potency. and efficacy.
`ACTION VS EFFECT—The effect of a drug is an alteration
`offlinctton ofthe structure or process upon which the drug acts.
`It is common to use the term action as a synonym for echct.
`However. action precedes eti'ect. Action is the alteration ofcon-
`ditfoa that brings about the effect.
`The final effect ofa drug may be far removed from its site of
`action. For example, the diuresis subsequent. to the ingestion of
`ethanol does not result from an action on the kidney but instead
`from a depression of activity in the region ofthe hypothalamus.
`which regulates the release of antidiuretic hormone from the
`posterior pituitary gland. The alteration of hypothalamic func-
`tion is, of course. also an effect” of the drug, as is each subse-
`quent change in the chain ofevents leading to diuresis. The ac—
`tion of ethanol was exerted only at the initial step. each
`subsequent effect being then the action to a following step.
`MULTIPLE EFFECTS—No known drug is capable of ex-
`erting a single effect. although a number are known that ap-
`pear to have a single mechanism ot'action. Multiple effects may
`derive from a single mechanism of action. For example. the. in—
`hibition of acetylcholincstcrase by physostigmine will elicit an
`effect at every SlILL‘ where acetylcholine is produced.
`is poten-
`tially active. and is hydrolyzed by cholinesterase. Thus.
`physostigmine elicits a constellation of effects.
`A drug also can cause multiple effects at several different
`sites by a single action at only one site, providing that the func-
`tion initially altered at the site ofaction ramilies to control other
`functions at distant. sites. Thus. a drug that suppresses steroid
`synthesis in the liver may not only lower serum cholesterol. ll‘l'l-
`pair nerve myelination and function, and alter the condition of
`the skin tas a consequence ofcholesterol deficiencyl but also may
`al'l'ect digestive functions (because of‘a deficiency in bile acids]
`and alter adrenocortical and sexual hormonal balance.
`
`1142
`
`-IAi-_._.._
`
`
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`MYLAN INC. EXHIBIT NO. 1035 Page 4
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`MYLAN INC. EXHIBIT NO. 1035 Page 4
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`

`

`CHAPTER 5?: DRUG ABSORPTION, ACTION, AND DISPOSITION
`
`1143
`
`critical balance. of the affected l'unction is that of' the mercurial
`diureticdrugs. An inhibition ol‘only l‘Ii- in the tuhular resorption
`of'glomerular lift-rate usually will tlouhle urine. flow. since 99".}:: of
`the glomerular filtrate is normally resorhed. Aside. from the
`question of’thc. possible concentration of'diuretics in life urine. :1
`drug-induced reduction of 1’-’r
`in sullhydryl enzyme activity in
`tissues other than the kidney usually i.-.- not accompanied by an
`observable change in function. Selectivity also can he deter-
`mined hy the pattern ofdistribution t'it'iiiat’tivuting or activating
`enzymes among the tissues and by other factors.
`DOSE—Even the. uninitiated person knews that the dose. of
`a drug is the. amount administered. However. the. appropriate
`dose of‘a drug is not some unvarying(plantity. ‘1 fact sometimes
`overlooked by pharmacists. official committees. and physicians.
`The practice of pharmacy is entrapped in a system ol’ fixed—dose
`formulations. so that line adjustmel'its in dosage are often {lifti-
`cult to achieve. Fortunately. there is usually a rather wide lat-
`itude allowable in dosages. It is obvious that the size ol'the re~
`Cipient individual should have a bearing upon the dose. and the
`physician may elect to administer the drug on a hotly—weight or
`surface-area basis rather than as a fixed dose. Usually. him-u
`ever. a fixed dose is given to all adults. unless the adult is ex-
`ceptionally large or small. The dust.- for infants and children of
`too is determined by one of several formulas that take into
`account age. or weight. depending on the age group of the child
`and the type of action exerted Iiy the drug. Infant's. relatively.
`are more sensitive to many drugs. often because systems in-
`volved in the inactivation and elimination ofthe drugs may not
`be developed fully in the infant.
`The nutritional condition of the patient. the. mental Outlook.
`the presence o'l’pain or discomlhrt. the severity ofthc condition hc‘
`ing treated. the. presence ofsecondary disease or pathology. and
`genetic and runny other factors affect. the dose t'lfl'l drug necessary
`to achieve a given therapeutic response or to cause an untm 'artl
`effect {Chapter 61 l. Even two t-lppurentlv well‘motclwd normal
`persons may require widely diflierent. doses for the same intensity
`of'eli'et‘t. Furthermore. a drug is not always employed for the some
`effect and. hence. not in the same dose. For example. the dose of
`a progestin necessary for an oral contraceptive effect is consider-
`ably different from that necessary to prevent. spontaneous abor~
`tiun. and a dose oft-1n estrogen for t he treatment ot’the menopause
`is much too small for the treatment ot’prostatic turcinoma.
`From the above, it is evident that. the. wise physician knows
`that the dose oft: drug is not a rigid quantity but rather that
`which is necessary and can he tolerated and individualizes the.
`regimen accordingly. The. wise pharmacist also recognizes that
`official or manufhcturers recommended doses are sonictii‘nes
`quite narrowly delinod and should serve only as a useful guide.
`rather than as an imperative.
`PDTENCY AND EFFICACY—The potency of :1 drug is the
`reciprocal of dose. Thus. it will have the units of" personsfunit
`weight Iil'drug or hotly weightfunit weight ufdrug. etc. Pottuicy
`generally has little utilityr other than to provide a means oft-oin-
`paring the relative activities of'drogs in a series, in which case
`refotice potency. relative to some prototypic In einbc r of the se~
`ries.
`is a parameter commonly used among1r ph:Irmucologists
`and in the pharmz-iceutical industry.
`Whether a given drug is more potent than another has little
`bearing on its clinical usefulness. provided that the potency is
`not so low that. the. size of the dose. is physically unmanageable
`or the cost of treatment is higher than with an equivalent. drug.
`[fa drug is less potent but more selective. it is the one to he. pre-
`ferred. Promotional arguments in favor of'a more potent drug
`thus are irrelevant to the important considerations that should
`gl'lvorn the. Choice of a drug. However, it sometimes occurs that
`drugs of' the same class differ in the maximum intensity of' of—
`feet; that is. some drugs ofthe class may he less efficacious than
`others. irrespective of how large a dose is used.
`Efficacy connotes the property of' a drug to achieve the dc—
`siretl response. and riiri.\‘iiiimii cfifir‘oev denotes the. maximum
`achievable effect. Even huge doses of codeine often cannot
`achieve the. relief from severe pain that relatively small doses
`
`MYLAN INC. EXHIBIT NO. 1035 Page 5
`
`Figure SM. The absorption, distrrbution, action. and elimination Cll' a
`drug lal'rowfi represent drug movement}. Intravenous administration IS
`the only process by which a drug may enter a con-ipanment without pass-
`intj through a biological membrane Note that drugs excreted in bile and
`saliva may be resoroed.
`
`Although a single action can give rise to multiple effects.
`must drugs exert multiple actions. The various actions may be
`related. as for example= the syn: pathomimetic eli'ects ol'
`plienylephrinc that accrue to its structural similarity to nore-
`pincphi‘inc and its ability to exert. sympathetic responses, or
`the actions may he unrelated. as with the actions of morphine
`to interfere With the release ol’acetylchnline from certain auto—
`nomic nerves. block some actions of5~hydroxyti‘yptamine isero—
`toninl. and release histamine. Many drugs bring about ini-
`munological tallergic or hypersensitivityi responses that bear
`no relation to the other ph arm acodyn amic actions of the drug.
`SELECTIVITY—Despite the potential most drugs have for
`elicitingr multiple effects. one effect is generally more. readily
`clicitahle than another. This differential responsiveness is
`called selectiiv'tv. it usually is considered to be a property ofthe
`drug. but it is also a property ofthe constitution and biody~
`namics off he recipit-int sul'ijeet or patient.
`Selectivity may come about in several ways. The suhcellulai'
`structure lreceptorl with which a drugr combines to initiate one.
`response may have a higher affinity for the drug than that for
`some other action. Atropine, for example. has a much higher
`allinlty for muscarinie receptors that suhsen‘e the function of
`sweating than it does for the nicotinic receptors that subserve
`voluntary neuromuscular transmission. so that suppression of
`sWeating can be achieved with only a tiny fraction ol‘ the dose.
`necessary to cause paralysis ofthe skeletal muscles. A drugmay
`be. distributed um:venly. so that. it reaches a higher concentra—
`tion at one site than throughout the tissues generally: chlol‘o‘
`quine is much more ellcctivo against. hepatic than intestinal
`lcolonicl amehiasis because it. reaches a much higher concentrzr
`lion in the. liver than in the wall of the colon. An affected func—
`tion may be much more critical to, or have less reserve in. one or—
`gan than in another. so that a drug will he predisposed to elicit
`an effect at the more critical site. Qionic inhibitors ol'dopa decor-
`boxylase which is also 5—hydroxytryptophan decarboxylase} de—
`press the synthesis of histamine more than that of either norc—
`pinephi‘ine or 5- hydroxyti‘yptamine [serotoninh even thOugh
`histidine de ’arhoxylase is less sensitive to the. drug. simply be-
`cause liistidine decarhoxylase is the only step and, hence, is rate-
`limiting in the biosynthesis ofhistamine. Dopa decarhoxylase is
`not rate. limiting in the synthesis oi’either norepinepl‘it'ii‘ie or 5—
`hydroxytryptnminc until the enzyme is nearly completely inhib—
`itcrl. Another example ofthe determination olisolectiyity by the
`
`Vast-5|
`
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`
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`UMNE
`
`MYLAN INC. EXHIBIT NO. 1035 Page 5
`
`

`

`1144
`
`PART 6'. FHARMACODYNAMICS AND PHARMACOKINETICS
`
`
`T
`l— ‘—|_
`I
`y— Gaye-Icicle = tron-mum after :
`
`I40
`
`:7) O
`
`ory It is necessary to define two types ofrclationships: {1} dose—
`intensity relationship, ie. the manner in which the intensity ofef-
`feet in the individual recipient relates to dose, and {2) dose—
`frequency relationship, ie, the manner in which the number of
`responders among a population of recipients relates to dose.
`DOSE—INTENSITY OF EFFECT RELATIONSHIPS—
`Whether the intensity of effect is determined in rice leg. the
`blood—pressure. response to epinephrine in the human patient]
`or in euro leg, the response of the isolated guinea pig ileum to
`histamineJ. the dose—intensity ofellizct. {often called dose—effect]
`curve usually has a characteristic shape, namely a curve that
`closely resembles one quadrant ofa rectangular hyperbole.
`In the dose-intensity curve depicted in Figure 57—2. the
`curve appears to intercept thex axis at I) only because the lower
`doses are quite small on the scale of the abscissa. the smallest
`dose being 1.5 x 10 "‘ pg. Actually, thex intercept has a positive
`value, since a finite. dose ol‘dr'ug is required to bring ahnut a re-
`sponse. this lowest effective dose. being known as the threshold
`dose. Statistics and chemical kinetics predict that the curve
`should approach they axis :‘tsymptotzieally. However. if the in-
`tensity of the measured variable does not start from zero‘ the
`curve possibly may have a positive y intercept lol' negative 1' in-
`tercept}, especially ifthe ongoing basal activity before the drug
`is given is closely related to that induced by the drug.
`In practice, instead of an asymptote to the y axis. dose-in-
`tensity curves nearly always show an upward concave foot at
`the origin ofthe curve, so that the curve has a lopsided sigmoid
`shape. At high doses. the curve approaches an asymptote that
`is parallel to the .t axis. and the value of the asymptote estab-
`lishes the maximum possible response to the drug. or maximum
`efficacy. However. experimental data in the regions of the
`asymptotes generally are too erratic to permit an exact defini-
`tion ofthc curve at very low and very high doses. The example
`shown represents an unusually good set of data.
`Because the dose range may be 100- or moo-fold from the low-
`est t0 the highest closet it has become the. practice to plot rinse-inv
`tensity curves on a logarithmic scale of abscissa tie, to plot the
`log of dose versus the intensity ofell‘ecti. Figure 57—3 is such a
`semilogarithmic plot ofthe same data used in Figure 57-12. In the
`figure the. intensity of effect is plotted both in absolute units tal
`the left} or in relative units, as percentages lot the righti.
`Although no new information is created by it seniilugm‘ith-
`mic representation, the curve is stretched in such a way as to
`facilitate the inspection of the data; the comparison of results
`
`
`
`k‘uv-asv hesitates rnaxlmurn effect =- maximum-efficacy
`
`
`
`
`—2
`
`--i
`
`IC'O
`
`or-.1c:or
`
`MU‘
`
`
`
`PERCENT0FMAXIMUMEFFECT
`
`50
`
`
`
`
`
`
`
`INCREASEINBLOODPRESSURElrnrnl-iqlsa
`
`or OF—x—osymptoie=thresholddose
`
`20
`
`
`o
`lo
`20
`so
`no
`so
`so
`To
`
`DOSE (fig/kg)
`
`Figure 57-2. The relationship at the intensity of the blood-pressure re—
`sponse oi the cat to the nitravenous dose of norepineohrme
`
`ofmorphine can: thus: codeine is said to have a lower maximum
`efficacy than morphine. Efficacy is one nfthe. primary determi—
`nants of the choice of a drug.
`
`DOSE-EFFECT RELATIONSHIPS
`
`The importance of knowing how changes in the intensity of re—
`sponse to a drug vary with the dose is virtually self-evident. Both
`the physician. who prescribes or administers a drug. and the
`manufacturer. who must package the drug.r in appropriate dose
`sizes. must translate such knowledge into everyday practice.
`Theoretical or molecular pharmacologists also study such rela—
`tionships in inquiries into mechanism of action and receptor the.—
`
`I40
`
`a:O
`
`O D
`
`
`
`
`
`
`
`INCREASEINBLOODPRESSURE(mmHg: 0'!0.1OO
`
`Figure 57-3. The relationship oi the intenaty ol the blood-pressure response of the cat to the log of the intravenous dose at norepineplinne
`
`LOG DOSE {logpglkgl
`
`MYLAN INC. EXHIBIT NO. 1035 Page 6
`
`———J—.___
`
`MYLAN INC. EXHIBIT NO. 1035 Page 6
`
`

`

`
`
`CHAPTER 5?". DRUG ABSORPTION. ACTION. AND DISPOSFTION
`
`1145
`
`from multiple obscn’ations and the testing of different drugs
`also is rendered easier. In the example shown. the curve is es—
`sentially what is called a sigmoid cores? and is nearly symmet—
`rical about. the point that represents an intensity equal to 50'}?
`of the maximal effect tie, about. the niidpointl. The syntt‘nctry
`follows from the rectangular hyperbolic character ofthe previ-
`ous Cartesian plot tsee Fig 57—2}. The scmilogarithmic plot re-
`veals better the dose‘ciicct relationships in the low—dose range.
`which are lost in the. steep slope ofthe Cartesian plot. Further—
`more. the data about the midpoint. are almost a straight”. line:
`the nearly linear portion covers approximately 50¢? oi the
`curve. The slope oi'the linear portion ot'the curve or. more cor-
`rectly. the slope at the point ot‘inflection. has theoretical sig~
`nificnnce tsee Drug Receptors and Receptor Theory J.
`The upper portion of the curve approaches an asymptote.
`which is the some as that in the Cartesian plot. If' the response
`system is completely at rest. before the drug is administered. the
`lower portion ot'the curve. should he asymptotic to the .1‘ axis. Both
`asymptotos and the symmetry derive from the. law ofmass action.
`Dose-intensity curves often deviate from the ideal configura-
`tion illustrated and discussed above. Usually. the deviate curve
`remains sigmoid but not extended sym metrically about the mid-
`point of the [incur segment. Occasionally. other shapes occur.
`Deviations may derive from multiple actions that converge upon
`the some final effector system. from varying degrees of
`metabolic alteration of the drugr at different doses. from modu-
`lation oft-he. response by feedback systems. from nonlinearity in
`the relationship between action and effect, or from other causes.
`It is frequently necessary to identify the dose that elicits a
`given intensity ot'eficct. The intensity ot'eii'ect that is gene 'ally
`designated is one of maximum intensity. The corresponding
`dose is cal led the 50"} effective dose. or individual E350 [see Fig
`iii—3!. The use of the adjective indim'dooi’ distinguishes the
`EDSU based upon the intensity ot'ei‘t'ect from the. median effec-
`tive dose. also abbreviated EDBD. determined from Frequency of
`response data in a population [see Dose-Frequency Relation-
`ships. this chapter}.
`Drugs that elicit the same quality oi'eit'ect may be compared
`graphically. In Figure 57—4. live hypothetical drugs are com-
`pared. Drugs A. B. C. andE all can achieve the some maximum
`eil'cct. which suggests that the same effector system may be
`common to all. D possibly maybe working through the same ef—
`fector system. but there are no a priori reasons to think this is
`so. Only-A and B have parallel curves and common slopes. Coni-
`mon slopes are consistent with. but in no way prove. the idea
`that A and 8 not only act through the some effector system but
`also by the same mechanism. Although drug—receptor theory
`isee Dray.I Receptors and Receptor Thcoryi requires that the.
`curves of identical mechanism have equal slopes. examples oi‘
`exceptions are known. Furthermore, mass-law statistics re—
`quire that all simple drug-receptor interactions generate the
`some slope; only when slopes depart from this universal slope
`in accordance with distinctive characteristics or the response
`system do they provide evidence of specific mechanisms.
`The relative potency ot'any drug may be obtained by dividing
`the E1350 of'tbe standard, or prototypic, drugr by that ot'thc drug
`
`
`
`
`
`in question. Any level ol'eficct. other than 50"} may he used. but
`ilehould be recognized that when the slopes are not parallel. the
`relative potency depends upon the intensity oi‘ effect cl'iosel'i.
`Thus. the potency oFA relative toCtsee Fig 57—4lcalculated from
`the. EDBD will be smaller than that calculated ii'om the EIJQS.
`The low maximum intensity inducible by i) poses even more
`complications in the determination of relative potency than do
`the unequal slopes ofthe other drugs. [fits dose-intensity curve
`is plotted in terms ot'pcrccntage ol‘its own maximum etioct. its
`relative inetiicacy is obscured. and the limitations oi’ relative
`potency at the E1350 level will not be evident. This dilemma Lin-
`derscores the fact that drugs can be compared better from their
`entire dose-intensity curves than from a single derived number
`like EDfiG or relative potency.
`Drugs that elicit multiple ei‘lccts will generate n dose‘inten-
`sity curve for each ei'l‘ect. Even though the various clihcts in my
`be qualitatively different. the sevc ‘nl curves may be plotted tn~
`gather on a common scale o'l'ahscissu. and the intensity may be
`expressed in terms of percentage of maximum elicctz thus. all
`curves can share a common scale of ordinates in addition to a
`common abscissa. Separate scales of ordinates could he em-
`ployed. but. this would make it harder to compare data.
`The selectivity oft-1 drug can be determined by noting what
`percentage of maximum of one effect can he achieved Deliarc a
`second efi‘ect occurs. As with relative potency. selectivity may
`be expressed in terms ot'tiie i':-1tiolil;~tween the EDSO for one ei‘w
`Feet and that For another uii’ect. or a ratio at some other inten—
`sity ot‘ eti'cct. As with relative potency. difficulties follow tron]
`noopal'allclism. In such instances, selectivity expressed in dose
`ratios varies From one intensity level to another.
`When the. dose—intensity curves for a nu in her of subjects 311'
`compared. it. is found that they vary considerably from individ—
`ual to individual in many respects; eg. threshold dose. mid—
`point. maximum intensity. and sometimes even slope. By aver—
`aging the intensities of the effect at each dose. an average
`dose—intensity curve can be constructed.
`Average dose—intensity curves enjoy a limited appli 'ation in
`comparing drugs. A single line expressing an average response
`has little value in predicting individual responses unless it is ac—
`companied by some. expression of the range oi'thc ci‘iecl at the. var—
`ious doses. This may be done by indicating.r the standard error oi‘
`the response at each dose. Occasionally. a simple scatter diagram
`is plotted in lieu of an average. curve and statistical parameters.
`An average dose—intensity curve also may be constructed from a
`population In which dim-rent. individuals receive difierent doses:
`it‘sutficicntly large populations are employed. the average cur\.'es
`determined by the two methods will approximate each other.
`It is obvious that the determination of such average curves
`from a population large enough to be statistically meaningful
`requires a great deal of work. Retrospective clinical data {ices-
`sienallg are treated in this way, but prospective studies infre-
`quuutly are designed in advance. to yield average curves. The
`usual practice in comparing drugs is to employ a quantal tall—
`or-nonoi endpoint and plot. the Frequency or cumulative l'l'e—
`quency of response over the dose range. as discussed below.
`DOSE—FREQUENCY OF RESPONSE RELATION-
`SHIPS—When an endpoint is truly all-or-none. such as death. it
`is an easy matter to plot the number of responding individuals
`ieg, dead subjects: at each diisc.ofdn1g or intoxicant. Many other
`responses that vary in intensity can be treated as all-nr‘none it
`simply the presence or absence of a response leg. cough or no
`cough. convulsion or no com-vision} is recorded. without i‘egi-u‘d
`to the intensity of the response when it occurs. When the re-
`sponse changes from the. basal or control state in a less abrupt
`manner tug. tachycardia. miosis. rate oi‘gastric secretion 1. it may
`be necessary to designate arbitrarily some particular intensity ol‘
`etiizct as the endpoint. II the endpoint is taken as an increase in
`heart rate ot‘2t) beatshnin. all individuals whose tachy‘ardia is
`less than 20 beatsfmin would he recorded as oonrespontlers,
`while all those with 20 or above would be recorded as responders.
`When the percentage of responders in the population is plotted
`against. the dose, a characteristic dose—response curve. more
`
`MYLAN INC. EXHIBIT NO. 1035 Page 7
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`r—i—v—i'.""."'|_|'—l—l—l'"rm—
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`
`INTENSITYOFEFFECT
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`//
`
`6‘
`,/"f
`
`E
`i
`
`D
`
`4—- OO
`
`‘d
`
`g(n
`
`M 01
`
`0
`
`PERCENTOFMAXIMUM
`
`RESPONSEOFDRUGA
`
`/LOG DOSE
`
`Figure Sit-4. Log dose—:nteosnv oi effect Curves of il'u'E‘ dittereol hypo-
`thetical druos {see text for explanation:
`
`MYLAN INC. EXHIBIT NO. 1035 Page 7
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`

`

`1145
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`2‘i—‘ART 5: PHARMACODYNAMICS AND PHARMACOKPNETICS
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`'30
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`2.10-—
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`0/0OFANIMALSTHATCONVULSED
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`
`
`/ED 5‘} =322 mgr’Kg
`
`i2
`
`I3
`
`t4
`
`i5
`
`it}
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`i?
`
`IS
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`Loo DOSElIog rng/kgl
`
`Figure Sit-5. The relatuonship of the number oi responders in a popula—
`tion oi mice to the dose at pentylenetetrazole.
`
`properly called a dosc‘rumttfotit‘c frequency or closrepi-it‘cenloge
`curve. is generated. Such a curve is. in fact. a cumulative fre-
`t]uency—distributii‘m curve. the percentage of responders at. a
`given duse being the frequency of res ponsc.
`Dose—Cumulativu frequency curves are generally ofthe same
`geometric shape as (lose-intensity curves tnaoiely. sigmoid:
`when frequency is plotted against log dose tFig 57—51. The ten—
`dency ufthe cumulated frequency of response tic. percentage! to
`he thwarly proportional to the log of the dose in the middle of the
`dose range is called the ll’ehri'-Fei.-litier Into, although it is not in-
`amiable. 'is a true natural law should be. in many instances. the
`cumulative frequency is simply proportional to (lose rather than
`lugr dose. The Weber-Fochm—H' law applies to either dose-intensity
`or dose—cumulative frequency data. The similarity between
`(lose-frequency and (lose—intensity curves may be more than for-
`tuitous. since the intensity of response will usually have an ap-
`proximately linear relationship to the percentage of responding
`tmits [smooth muscle cells, nerve fibers. etc! and. hence. is also a
`type of cumulative frequency of response. These are the same
`kind of statistics that govern the law ofmass action.
`If only the increase in the number of' responders with each
`new close is plotted. instead of the cumulative percentage of re—
`spnnders. a hell~shaped curve is obtained. This curve is the first
`derivative. of the dose—cumulative frequency curve and is a fi'e-
`quellor-tfislrihation curve. The distribution will be symmetri-
`cal—ic. normal or Gaussian tsee Chapter 123—only ii‘ the
`dose—cumulative frequency curve. is symmetrically hyperbolic.
`Because most dose—cumulati\-'e frequency curves are. more
`nearly symmetrical when plotted sentilogarithmically tic. as log
`dose]. dose—Cumulative frequency curves are usually fogvm'u‘niof.
`Since the dose—intensity and dose—cumulative frequency
`curves are hasicnlly similar in shape. it fiJllows that. the curves
`have similar defining characteristics. such as EDSU, m