'51
`
`215T EDITION
`
`Remington
`
`
`
`The Science and Practice
`
`of Pharmacy
`
`é% LIPPINCOTTWILLIAMS a‘W[u<.IN5
`'
`A Wolters Kluwer Company
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`A1\/[NEAL
`
`EXHIBIT N0. 1035 Page 1
`[[1
`
`

`
`
`
`Editor: David B. Troy
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Marisa A. O’Brien
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`material contained herein. This publication contains information relating to general principles of medical care which should not
`be construed as specific instructions for individual patients. Manufacturer’s product information and package inserts should be
`reviewed for current information, including contraindications, dosages and precautions.
`
`Printed in the United States of America
`
`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
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
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`Copyright 1956. 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Philadelphia College of Pharmacy and Science
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`Copyright 2000, 2006, by the University ofthe Sciences in Philadelphia
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`All Rights Reserved
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`ISBN 0-7317-4673-6
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`The use ofstructural formulas firom USAN and the USP Dictionary offlrug Names is by permission ofThe USP Convention. The
`Convention is not responsible for any inaccuracy contained herein.
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`Notioe—Tl1 is text is not intended to represent, nor‘ shall it be interpreted to be, the equivalent ofor a substitute for the ofiiciol
`United States Phorrnocopeio (USP) andIor the National Formulory (NF). In the event ofany difiizreiice or discrepancy between the
`current official USP or NF standards ofstrength, quality, purity, packaging and labeling for drugs and representations ofthern
`herein, the con text and efi"ect of the official compendia shall prevail.
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`Al\1NEAL
`
`EXHIBIT NO. 1035 Page 2
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`12345678910
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`

`
`. A treatise on the theory
`Remington: The Science and Practice-of Pharmacy. .
`and practice of the ,oharmaceuticai sciences, with essen tiai
`ihformation about pharmaceutical and medicinai agents,‘ also, a
`guide to the professional res,oonsibiIities of the pharmacist as the
`drug information specialist or‘ the health team .
`.
`.. A textbook and
`reference work for pharmacists, physicians, and other practitioners or
`the pharmaceu ticai and medicai sciences.
`
`EDITORIAL BOARD
`
`Paul Beringer
`
`Pardeep K. Gupta
`
`Ara Derlviarderosian
`
`John E. Hoover
`
`Linda Felton
`
`Steven Gelone
`
`Nicholas G. Popovick
`
`William J. Reilly, Jr
`
`Alfonso R. Gennaro
`
`Randy Hendritkson, 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—i'irst Edition—2005
`
`Published in the 185th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`AMNEAL
`
`EXHIBIT NO. 1035 Page 3
`
`

`
`
`
`-‘Michael E Franklin. -Pl] D".
`'-l“lo_n‘a.ld N Frs_ns.-,Pli‘E3!
`
`C H A 1=T.-'EjR.-'
`
`
`
`Although drugs difli-r widely in their pharmacodynamio effects
`and clinical applications; in penetration. absorption, and usual
`route of3Cl.lI1i.I1‘lStl1'al.iOl'i.'_ 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 phannaceutic and therapeutic im-
`plications. They facilitate an understanding of both the fea-
`tures that are common to 3 class of drugs and the differences
`among the meinbers oft-hat class.
`For a drug to act. it must be absorbed. transported to the ap-
`propriate tissue or organ. penetrate to the responding cell 51.11‘-
`
`face or subcellular structure, and elicit a response or alter on-
`going processes. The drug maybe distributed siniultaneouslyor
`sequentially to a number of tissues, bound or stored, metabo-
`lized to inactive or active products, or excreted. The_histo1*-y ofa
`drug in the body is summarized in Figure 57-1. Each of the pro-
`cesses or events depicted relates importantly to therapeutic
`and toxic effects ofa drug and to the mode of administration,
`and drug design must take each into account. Since the elfcci
`elicited by adrug
`its raison I:Z’étre, drug action, and office: are
`dJ'.scussed_fi1:s1: in. the text that follows, even
`they
`preceded by other events.
`
`IIIIIIG ACTION AMI! EFFECT
`
`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 of the recipient
`of the 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.. [Studies indicate that pain is not simply
`the ;rercepo‘on of a certain kind of stimulus but rather, a reac-
`tion to the perception of a variety of kinds of stimuli or stimu-
`lus ]:Iat.tcrns.'l Both because the pertinent properties are locked
`into the complex and somewhat imprecise biological context
`and because the types of possible response are many, descrip-
`tions ofthc prn'pcr‘l:ics ofdrugs tend to emphasize the qualita-
`tive Features of the effects they elicit. Thus, 3 drug may be de-
`scribed as having analgesic. vasodepressor. convulsent,
`antibacterial, etc. properties. The specific elifect (or use} cate-
`gories intowhich 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 of a drug does not and with
`the enumeratio_n of the responses it may elicit. There are cer-
`tain intrinsic properties of the drug-recipient system that can
`he described in quantitative tor ms and that are essential to the
`full description of the drug and to the validation oftho drug for
`specific uses. Under Definitions and Concepts below. certain
`general terms are defined in qualitative language; under Dose-
`Efiéct Relotio.o.s.F1'Eps, the foundation is laid for an appreciation
`of some of the quantitative aspects of pharmaoodynaruics.
`
`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 few definitions that areimportant to the proper un-
`
`derstanding of pharmacology. It is necesary to difi'e-rentiate
`among action, efl'ect, selectivity, dose, potency, and efficacy.
`ACTION VS EFFECT—'I‘l1e effect of a drug is an ogltsratiiin
`offunction ofthe structure or process upon which the drug acts.
`It is common to use the term action as a-synonym for effect.
`However, action precedes effect. Action is the alteration. of'con-
`dition that brings about the effect.
`The final effect of a 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 of the hypothalamus,
`which regulates the release of antidiuratic hormone froin the
`posterior pituitary gland. The alteration of hyp'otlialamic func-
`tion is. of‘ course. also an effect of the drug. as is each subse-
`quent changc in the chain of events leading to diuresis. The ac-
`tion of ethanol was exerted only at the initial step, Each
`subsequent effect being then the action to--e following step.
`MULTI1“LE 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 of action. Multiple eifects may
`derive from a single mechanism of action. For example, the in-
`hibition of acetylcholineaterase by physostigmine will elicit an
`effect at every site Where aoetylchnline is produced, is poten-
`tially active. and is hydrolyzed by cholinest-erase. Thus.
`physostigroine 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 ramifies to control other
`fimctions at distant sites. Thus, a drug th at suppresses steroid
`synthesis in the liver may not only lcrwer serum cholesterol, im-
`pair nerve myelinstion and fiuiction. and alter the condition of"
`the slcin (as a. oonssqusnm ofcholesterol deficiency) but also may
`affect digestive functions [because of a deficiency in bile acidsl
`and alter atirenocortical and sexual hormonal balance.
`
`‘I142
`
`ARINEAL
`
`EXHIBIT NO. 1035 Page
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`

`
`SITEOF‘ICTION
`
`CHAPTER 571 DRUG l'-'lB50RP'l'10N. ACTION. AND DISPOSITION
`
`1143
`
`critical balance of the affected function is that of the mercurial
`diuretic drugs. An inhibition ofonly 1% in the tu bular resorption
`oi‘glamer.t1lar filtrate usually will double urine flow, since 99% of
`the glcirrterulaz" filtrate is normally roaorbed. Aside from the
`queatioo oftlle poasible can-£i£!1_11:rati'on of diuretics in the urine. :1
`drug-iniiuoed reduction of liiiv i_u sulfliyclryl enzyme activitaj in
`tissues. other than thekiduey usually is not accompanied by an
`obsenrable change in function. Selectivity also can be deter-
`mined by the pattern ofcliotribution uf"ina'ct-ivating or o.ct.ivati.i1g
`enzymes among the t-issues and by otltet‘ factors.
`DOSE—Even'l:he uninitiated person knows that the dose of‘
`a drug is the anlount administered. However. the appropriate
`dose ofa drug is not some uiwarying quantity. a fact sometimes
`overlooked by pharrn acioto. officicl committees. and physicians.
`The practice of pharmacy is entrapped in a s_~,r-stem" oi‘ fixed-dose
`l'or'ri1ulatious..su that fine adjustments in dosage are often diffi-
`cult to aotiieve. Fortunately. there is '|.lSt.lEil.l_'\l' a rather wide lat-
`itude allowable in dosages. IL is obvious l.l1n.t. the size of the re-
`cipient individ;.1al,sl'1ould have a bearing upon the dose. and the
`phyeicien may elect to administer the drug on a body-weight or
`aurface-area basis rather than as a fixed dose. Usually, l.1r.rW-
`cver, a fixed dose is given to all adults, unless the-adult is ex-
`ceptionally large or small. "The dose for infants and children of‘-
`ten is determined by one of several formulas that take into
`account age or weight. depending on the agegmup ofthe child
`and the type" of action exerted by the drug. Infants. relativelgir.
`are more sensitive to many drugs, often because systems in-
`volved in the inactivation and elimination ofthe drugs may not.
`be developed ‘lLlll.)? in the infant.
`_
`The nutritional condition of the patient. the mental outlook.
`the presence ofpain or discomfort, the severity ofthe condition be-
`ing treated. the presence ofseoondary disease or pathology. and
`genetic and many other Factors allectthe dose ofa drug necessary
`to achieve at given therapeutic response or to-cause-an untoward
`elfecl: {Chapter fill. Even two app.arentl_v we'll-inatclicxi normal
`persons may require widely difl"ei-entrluses for the same intensity
`ofeflect. Fiirtliei-more. adrog is not always enioloyed for the same
`elfiect arid. hence. not in the same dose. For example. the dose of
`a progestin necessary for an oral contraceptive effeotie consider-
`ably diilerent from that necessary to prevent spontaneous abor-
`i.ion,and a dose of an estrogen for the Lreatment of‘the-menopause
`ie rimch too small for the treatment nfpmatm‘.-it carcinoma.
`From the EIl:3DYE.it1's evident that the wise physician knows
`that tire dose -of a drug. is not a rigid qoaritity but rather that
`which is necessary and can be tolerated -and iridividualizes the
`regimen accordingly. The wise [iharrrtncist also rt-:cUg'nl'ze.'.s that
`olficial or manufacturer’: recommended doses are simnetimes
`quite narrowly defined and should serve only as a useful guide
`rather than as an imperative.
`POTENBY AND EFFICACY—'I‘i1e potency of a drugie the
`reciprocal of dose. Thus. it will have the units of perfirins/unit
`weight of drug or body -Weightfunit weight l-it'cI"1'ul§. etc. Potency
`generally has little utility other than to provide a means o'f'con1-
`paring the relative activities of drugs in a series. in which case
`relortoe poienqi-. relative to some prototypic member of the sc-
`riea. ie a parameter commonly used among plmrm ecologists
`and in the pharmaceutical 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 ol't.11e-close is physically unmanageable
`or the cost "of treatment is higl'.i'er than -with an equivalent drizg.
`If a drug is less potent but more selective. it is the one to be pre-
`ferred. Promotional arguinents in favor etc more potent drug
`thusare irrelevant to the in'i1:iortant.considerationo that should
`govern the choice C-fa drug. However, it. sometimes occurs that
`drugs oi’ the same-class rl.il'f'e-r in. the maximum intensity iii‘ oil
`feet; that-is. some drugs of the class may he-less efficaciiius than
`others. irrespective of how large a dose is used.
`Effimcy connotes the property of a drug to achieve the dc-
`aired response, and rrtoxirimm cfi'ieoc_1' denotes the 11'iaxin:ii.1m
`achievable effect. Even huge doses of codeine often cannot
`achieve the relic-l'f'ro1n severe pain that relatively small doses
`
`ARINEAL
`
`EXHIBIT N0. 1035 Page 5
`
`Figure 5?-1- The absorption, distribution. action, and elimination of E!
`drug {arrows represent drug movement). Intravenous administration is
`the only process by which a drug may enter a corrioartnienl without pass-
`ing through a biological membrane. Note that drugs excreted in bile and
`saliva may be rosnrbed.
`
`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 5_'fl'l‘}1i‘:l.l..ll{‘.|i'i'llII!lE_l..llI.’ effects of"
`phunylephrine that accrue to its structural Similarity to nora-
`piiiephrine and its ability to exert sympathetic responses. or
`the actions may be unrelated. as with the ai:-tione ofmnrphine
`to interfere with the release ofacetylcholine from certain auto-
`nomic nerves. blocltaornc actions 0l'5-h3l'ElrD7i.Yl»l‘)'pl.flI1l.in'E l seru-
`toninl. and release histamine. Many drugs bring about irri-
`munological l allergic -or hypersensitirityl responses that bear
`no relation to the other pharuiacodynam'i'c actions of the flI’l.l;g.
`BELECTIVITY-'—Despite the potential most drugs have for
`eliciting multiple effects. one effect is generally more readily
`eliritable than another. This differential responsiveness is
`called selectivity. It usually is considered to be a property ofthe
`drug. but it is also a prup'erty- of the constittltion and bind)!-
`naruics oftlte recipient subject or patient.
`Selectivity they come about in Several ways. Tlrie auhcollular
`structure lreceptorl with wliieli a drug combines to initiate one
`response may have a higher affinity for the drug than that for
`somi: other action. Atropine. for example, has El much higher
`affinity for mttscarilric reccptoin that auboerve the function of
`sweating than it does for the niootinic receptors that subserve
`irolimtal-"3' n_eui.'omuscular transmission, so that suppression of
`sweating can he achieved with only a tiny fraction of the dose
`necessary to cause paralysis of the skeletal muscles. Adrug may
`be distributed unevenly. so that it reaches is higher concentra-
`tion at one site than throughout the tissues generally; chloro-
`quine is. much more effective against hepatic than intestinal
`{colonic} emehi asis because it reaches a much higher concentra-
`tion in the liver than in the wall of the-colon. A11 £Ifi’et:t.c-ll illne-
`tinn ma}-he much more critical to. or haveleas ‘reserve in, -{'.|'l1ED?-
`gas than in another. so that a drug will he predisposed to elicit
`anefihct at the more critical site. Smite inhibitors of dopa.de_car-
`hosjlase lwltich is also 5-ll_‘.-|'l2ll'l2i|X)Tt?!'}Vpl.'~DE|l1E!.l'l decarliioxylaeel de-
`press the synthesis of histamine more than that of either ‘nora-
`pineplirine or 5- hydroxytryptamine teerotorrin], even -though
`liistidine decarbnxylase is less sensitive to the drug. simply be-
`cause histidina decarboxylase is the only stop and. hence. is rate-
`limitingin the biosynthesis of histamine. Iilopa decarboxylase in
`not rate limiting in the synthesis cit‘ either norepinephrine or 5-
`llytlmxytryptomine until the enzyme is nearly completely inhib-
`itcrl.AnI:it.her example of the determination of selectivity by the
`
`iiiEtiiaoi.irss -.._‘
`E
`em»: or
`i
`i.ai.o1rir.mei=oiiiiiirrio,i'i
`
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`
`|
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`SITEOF‘ADMINlS‘l'Ril‘I'I'OH
`
`

`
`11-I4
`
`PART 6,: IHARMACOBYNAMICS-AND PHAR-M A:C0l<lNE1'-TCS
`
`,.,-.._-.-.
`.-.............-nu...
`Kr o5_y-1-'mI'o!e = rnonlr-u.mn emu! = elf,i:m_ly
`
`,
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`. . .-_
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`E
`
`
`
`INCH-Ell-SEINBLOODPRESSURE[mmHg!ll‘!05D_Cl
`
`
`
`
`
`30
`
`
`
`ojry It is nodes-my to -derme two types of relationships: I 1.) dose
`'i_n’senaityrelati'onahi_p, Ia.-the manngr in‘ which the intensity of'e.l'-
`feoi. in the individual reoipi-out relates to dose, and (2) dose-
`fi-equenoy relationship. ie, the manner in which the number of
`responders among a population ofreoipients relates to dose.
`_ D0‘Sl§I-1N'I'ENSITY OF EFFECT RELATIONSHIPS-
`Wfiethar the intensity of effect is 'datarn1in|:d in viva log. the
`blooipressure resporuze to epirnaphrine in the human patient}
`or an ultra leg. the response of the isolated guinea pig ileum to
`histamine}. the doserintensity‘ of effect (often called dos'e~efi"eo1_.}
`curve usually hat! a characbexristil: shape, namely H. curve that
`olosaly resembles one quadrant afa rectangular hygbei-bola.
`In the done-intensity curve depicted "in Figure 57-2, the
`curve appears to intercept the: axis at 0 0113)“ because the lower
`-doses are" quite small on the scale of the abscissa, the smallest
`-dose heizlg 1-5 I 10 "‘ ;.zg.Ao1.ua]Iy, tho: infiorco_pthao fl- lmoitrivo
`value, since a fihite dose of drug is 1-eqtfired to bring about la no
`spouse, this lowest. effective does: being known as the tklosflnfd
`-close. Statistics and chemical kinetics predict that. the curve
`ahoultt app-roach the 3 axis asymptotically. However, if the In-
`tonaity -of the meoaurcd variable dooa- not start from zero,. the
`om-ve possibly may have -a positivey intercept I or negative :4: in-
`tercept), especially if the ongoing basal aot.iv'i,ty before £112 drug
`is -given is closely related to that induced by the drug.
`In practice. instead of an asyinptute on the y axis, doae—in-
`tensity curves nearly always show an upward concave font at
`the
`of the curve, so that the-curve has a lopsided sigmoid
`shape. At high doses-. the curve approaches-an asymptote that
`is parallel to the 1 axis, and the value of the asymptote estab-
`1i.sl:u:'.s the maximum po,aaibl_a' response to the drug, or maximum
`efii om.-y. However, oxparimental -data in the regions of tho
`asymptotoa generally are too erratic to permit‘ an exact defini-
`tion of-the curve at. vary low and very high doses. The oxamplto
`shown representoan unusually -good set-ofdata.
`Becaua_et-.1-ye‘ dose range-m-oy be 100- or 10{)'(}rfol'ti from tholow
`eat to the highest dose, it has laettmne the practice in plot Iio:,:e~in-
`tensity-curves on a logarithmic scale ofobscissa lie, to plot the
`log-of dose versus the inteosity of effect]. Figure 57-Sis such a
`sonfilogafithnfio plot ofthe some data used in Fi-guru 57-52. In the
`figure the intensity o£'afi'éct is-plottod both in absolute units fat
`the left) or in relative units. as percentages (at the right].
`Although no new information is created by a semiEogan'th-
`mic representation, the curve is stretched in such a way as to
`‘facilitate the in.-spesttion of the data; the comparison of results
`
`30
`
`no
`
`DOSEU19/-|1_q)
`
`Figure 57-2. The relationship of the intensity of the bluo-,d-.pIé5surE ro-
`soonse of the cat to the qntravenous close of noreplnophone.
`
`of morphine can; thus. codeine is said to have .a lower maximum
`efii'::_a.v:.y than morphine. Effioacy is one ofthe primary dolomi-
`-nomts of the clmioe of’ st drug.
`
`DOSBEFFECT RELATIONSHIPS
`
`The importance of1mow'ing' how changes in ihe intensity of
`spouse to a drug vary with the dose is viz-ouo1Iysolf'-evident. Both
`the physician. who prescribes or administers a dnrg, and the
`manna:-f‘acI:urer, who must package the :1:-ug in appropriate dose
`sizes, must translate such "knowledge into everyday practice.
`Theomfical or molecular pharmacologists also such rela-
`tionships "in inquiries into mechanism-ofaction and receptor the»
`
`E D
`
`" ' ' '
`
`5
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`100
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`20
`
`Figure 5?-3. The reldtlunshsp of the mrensity of the l1iood—pn=_.-ssure response of the cat to me log of the intravefious dose of norepinephrine.
`
`ABINEAL
`
`EXHIBIT NO. 1035 Pag
`
`LOG DGGE(Ingj.ig!kg]
`
`

`
`CHAPTER 57: DRUG ABSORPTION. ACTION. AND DISPOSITION
`
`1.145
`
`in question. Any level ofeffuct other than 50% may be used. but
`itsbould be recognized that when the slopes are not parallel. the
`relative potency depends upon the ‘intensity ofeffect chosen.
`Thus, the potency of'A relative to C I see Fig 57-4) colculatetl from
`the ED50 will be oltmlliar than that caIcu]'a1.od Ffom tho ED25.
`The low toaximuru intensity inducible by D poses even more
`complioalions in the determination of relative potency than do
`the unequal slopes of the other drugs. lfifli dose"-intensity curve
`is plotted in l.-l.‘I'J.'l2|.‘i of percentage of its own maximum effect. its
`relative incflicacy is obscurei arid -the linnilatiorls of relative
`potency at tho ED5Cl level will not be Evident. This dilemma oo-
`derscores the fact that I:lrU.g‘c can be co-mporcd better from their
`entire dose-intensity curves than from a single derived number
`like ED50 or relative potency.
`Drugs that elicit multiple e'Ff'ec1.s will generate a close-inter»
`sity curve for each effect. Even though the various cfi"e.cLs may
`be qualitatively difl'eron.i;. the several curves may be plotted to-
`gether on "a common scale of abscissa. and the im.ensit_\' may be
`cxprcaocd. in terms of pI=.1‘cc-ntogc of maximum eiibct; thus. all
`curves can share :1 common scale of ordinates in addition to a
`common abscissa. Separate scales of ordinates could be cm-
`ployod, but this would make it.'|'1arI:lor to compare data.
`The selectivity of a drug can be dete1“1'rI.inetl by noting what
`percentage of maximum of one effect can be achieved before a
`second effect occurs. As W'll.l'l relative potency, selectivity 'm:i_v
`be expressed in te1'rns of the ratio bctwccn the E1350 for one of?
`feet and that for another effect-. or a ratio at some Ol:l1E!*lI1tE!l'1"
`city ofcffec-1;. As with relative potency, dil‘fic.ultics follow from
`nonparsllelism. In such instances. selectivity expressed in dost?
`ratios varies from one intensity level to another.
`When the dose-intensit.y curves for a number of subjects are
`compared, it is found that they vary consi_de-robly from lndivirl—
`ual to individual in mtlny respects; cg, threshold dose. mid-
`point. maximum inte-nsity,.and sometimes even slope. By.aver-
`aging the intensities of the effect at each dose. on average
`dose-in tensity curve can be constructed.
`Average dose-ijitcnsity curves enioy a limited application in
`comparing drugs. A single. line expressing an average response
`has little value in predicting individual responses Llnloss it is ac-
`oompaniod by some expression ofthe range of the c1"‘f'oc1; at the var-
`ious -doses. This may be done by indicating the standard error of
`the response at each dose. Occasionally, a dimple scatter diagraxn
`is plotted in lieu oflao. average GIITVE and statistical parameters.
`An average dose-intensity cu we also may be -wostcucted from s
`populationin which-different individuals receive difibrcnt doses:
`ifsufiiciently large populations are employed. the average cirrvcs
`dctonniocd bythc two methods will approximate each other.
`It is obvious that the determination of such cvc-"rage curves
`from a population large enough to be statistically meaningful
`roquires a -great deal of work. Retrospective clinical -data occa-
`sionally arc treated. in this way, but prospective studies 1-l1El"E*
`queutly are dcsigllcd in advance to yield average curves. The
`usual practice in comparing -drugs is to employ a quanta] loll-
`or-nonel onclpointsnd plot the fiequency or cumulative fro-
`qucricy of vespooso over the dose range, as discussed below.
`D'DSE—E‘REQUEN'CY OF RESPONSE RELATION-
`SHIPS-—-'Whe‘r1 an endpoint ‘is truly all-or-none. such as death. it
`is an easy matter to plot the number of responding individuals
`(cg, dead suhiectsl at each dose ofdrug or intoxicsnt. Many other
`responses that vary in intensity can be treated as all-or-none if
`simply the presence or absence of a vwponoc leg, cough or no
`cough, convulsion or no oonvulsioni is recorded. without regard
`to the intensity of the r-espouse when it occurs. When the re-
`sponse chsuges from the basal or control state in a less abrupt
`manncrleg, tachycardia, miosis, rate ofgastric secretion). it rmly
`be nocecsaiy to designate arbitrarily some particular intensrity of
`effect as the endpoinlz. lfthe endpoint is taken as an increase in
`heart rate of 20 bcatsfmin. -all individuals: whose tachycardia is
`less than 20 beats"/min would be recorded as uonresponzlers.
`while all thooewith 20 or above would be recorded ac responders.
`"When the percentage of responders in the population is plotted.
`*=-M--‘*-==* *1“ dam a characteristic dose—1'csponsc curve. more
`
`ARINEAL
`
`EXHIBIT N0. 1035 Page 7
`
`fmro multiple observations and the testing of difibrent drugs
`also is rendered easier. In the example shown, the curve is esr
`sentially what is called a s.'.'gmot'tf come and is nearly symmet-
`rical about the point that represents an intensity equal to 50%
`of the maximal efibci‘. lie, about the midpoint!‘ The symmetry
`follows from the rectangular hyperbolic cl1a1'actor of the previ-
`ous Cartesian plot [see Fig 57-2]. The semilogarithmic plot re-
`veals better the dose-effect relationships. in the low-dose range,
`which are lost in the steep slope of the Cartesian plo1...Furt11er-
`moro. the data. about the midpoioi are almost a straight line:
`the nearly linear portion covers approximately 50% of the
`curve. The slope ofthe linear portion of the curve or. more cor-
`rectly. the slope at the ‘point of inflection, has theoretical sig-
`oificonuc lace Drug Receptors and Rccvpfior 'I'?1cz)-f_*yl.
`The upper portion of the curve approaches an asymptote,
`wliich is the same as that in tho Cartcsiun plot. If the response
`system is completely at rest before the druflis administered, the
`lower portion ofzhe curve should be asymptotic to then: axis. Both
`asymptot-cs and-the symmetx-_-r derive from tholuw ofmoss action.
`Dose-intensity curves ofizcn deviate from the ideal coir:i'ig‘u1'a—
`tion illustrated and discussed above. Usually, the deviate curve
`remains sigmoid butnot exte oded symmetrically about the mid-
`point of the iinmr segment. Occasionally, other shapes occur.
`Deviations may do:-ivefi-om. multiple actions that converge upon
`the same final effector system, from varying degrees of
`metabolic alteration of the drug -at different doses. from modu-
`lation ofthe response by feedback systems, from nonlinearity in
`thcrEl.ntio11.sl1ip between action anI:l'efi'act,_ur froni other causes.
`It is t'rcquen1.‘Iy necessary to i dentify the dose that elicits a
`given intensity of effect. The intensity of eifect that is generally
`designated is sac of maximum intensity. The corresponding
`dose is called the '5El‘3E- effective dose. or individual: EDED (see Fig
`fi'i'~3l. The use of the adjective :in'c£EoEdual di'_ot.ir'1g‘ui5hco the
`EH50 based upon. the intensity of effect from the median effec-
`tivc-dose, also abbreviated ED50. determined fiomfrcquency of
`response data in a population {sec Dose-Frequency Relation-
`ships. this chapter).
`Drugs that elicit the some quality of eifoct may be compared
`Eraphically. In Figure 5124, five hypothetical drugs are com-
`pared.
`_ A, B. C, anclE all can achieve the-some maximum
`client, which suggests that the some clients: system may be
`common to all. 5' possibly may be working through the some ef-
`fector system. but there are no a prior!‘ reasons I50 think this is
`so. Cln,l_vA andB have parallel curves and common slopes. Com-
`mon slopes are consistent with. but in no way prove. the idea
`tham and 8 not only act through the some cEf'oc.tor system but
`also by the .5a.n'1c mechanism. Although drug-receptor tl'i.E_|2|I'j'
`(see Drug Receptors and Receptor Theory} requires that the
`wives of identical mechanism have equal s1cpes.cx-_amp]os of
`exceptions are known. Furthermore. mass-_la-.v 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 of the response
`system do they provide evidence ofspccific mechanisms.
`The relative potency of anydrugmaybe obtained by dividing
`tl1EED5(l of the otandoxcl. or prototypic, drugby that of‘ the drug
`
`}£|'-C
`
`mag‘
`243
`33
`(In
`5.‘
`no
`
`5‘?
`
`LDG DOSE
`
`26. on.
`um
`
`"5
`u:
`‘i
`Lu
`LL
`O
`
`I}.
`
`aE
`
`Ii
`..
`
`Figure SE4. Log-dose-Intensity of effect curves of frve different hyp_o—
`Ihatical drugs. (see text lor explanation).
`
`

`
`1148
`
`PART 5: FHARMACODYNAMJCS AND PHARMACOICINETICS
`
`
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`"laor-‘ANIMALSTHATCONVUL5-ED
`
`
`
`
`
`E0
`
`E0
`
`40
`
`SO
`
`2:")
`
`. 2:50:32: mgno;
`
`quency distribution is normal, the 131350 is both the arithmetic
`mean and the median dose
`represented by the 1_m'dpoi11i:.on
`the ciu~ve;'i1' the distribution is log-non-rial. the E1350 is=1:he me-
`dian close but not the arithmetic mean dose-. The’ effioacy is the
`cumt.11a1:ive- frequency summed over all doses; it. is usually. but
`not always, 100%. The slopeis characteristic ofboth the drug-and
`the teat population. Even two
`of identical rJ.'l_¢°«l_‘iB.ni51_:n may
`give riseto different slopes in dose-percentage curves. wlierteasiu
`dose-intensity curves the slopes are the-same.
`Statistical parameters {such as -standard deviation}, in addi-
`tion to E1351}, 1'nEIl.1l1l1lIl cumulative fiequency (eifi'cax:y) and
`slope. I::l:Iars,ot'erioe dose—cumulai:ive frequency relationships
`[see Chapter 12).
`There are -several formulatiions for dose—<:uI_nuletivo fre-
`quency curves, some -of .wh'o:h are employed only to define the
`linear .eegmen‘I; of :1. curve and to determine the st:-1I.isi.i.'t:al. pa-
`rameters oftlfis segnienlz. For the statistical treatil‘-‘flout of'd_ose-
`ii-eguency data. see Chapter 12. One simple mathematical ex»-
`pression of the entire log‘-sylnmetrical sigmoid curve is
`9|: response
`100% - response
`
`lug-ause = it +J'lug
`
`I11
`
`
`
`where peroantage- response may be either the percentage-of
`maximum intensity or the percentage of a population 1'espond—
`ing. The equation is thus basically the some for both log normal
`dose—int-snsity -and log normal dose-percentage relationships. is’
`is is constant that is ci1e.ract'orisl:ic oftfie miflpoint -ofthe curve.
`or EH50. and lff is oharactori"stion1ly related to the slope of the
`linear segment. which, in turn is closely related to the standard
`deviation of the derivative log-normal f‘1'equenoy~distribution
`I'.!'|,1.1‘VS.
`
`The comparison of dose~pe1‘oa11tage relationships among
`drugs is subject to the pitfalls indicated for dose-intensity com-
`parisons, namely, that when the -slopesnf the curves are not the
`same [ie. the dose-percentage curves are not parallel}. it is neo-
`essary to state at which level of response a potency ratio is cal-
`culated. As with do-so-intensity data. potonoies generally are
`oe'lc.ulat-ed from the-ED50, but potency ratios may be calculated
`for any arbitrary percentage response, The expression of saloo-
`tivityie,