T Remington's
`Pharmaceutical
`
`Sciences
`
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`17m
`EDITION
`
` Remington's
`
`ALFONSO R GENNARO
`Editor, and Chairman
`of the Editorial Board
`
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`
`A
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`42%/Q
`
`1985
`
`MACK PUBLISHING COPMANY
`E05100, Pennsylvania 18042
`
`TEVA EXHIBIT 1030
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`

`
`CHAPTER
`
`ibrug Absorption, Action, and Disposition
`
`Stewart C Harvey, PhD A
`‘Professor of Pharmacology
`‘
`School of Medicine, University of Utah
`Salt Lake City. UT 84102 -
`'
`
`'
`
`‘
`
`. Although drugs differ widely in. their pharmacodynamic
`effects and clinical application, in penetrance, absorption, and
`usual route of administration, 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 pharmaceutic and
`therapeutic implications. They facilitate an understanding
`of both the features that ‘are common to a class of drugs and
`the differentia among the members of that class.
`‘ -In order for a drug to act it must be absorbed, transported
`‘to the appropriate tissue or: organ, penetrate to the responding
`subcellular structure,_ and elicit a response or alter ongoing
`processes.‘ The drug may be simultaneously or sequentially
`distributed to a number of tissues; bound or stored, metabo-
`lized to inactive or active products, or excreted. The history
`of a drug in the body is summarized in Fig 37-1. Each of the
`processes or events depicted relates importantly to.thera—
`peutic and toxic effects of a drug and to the mode of admin-
`istration, and drug design must take each into account. Since
`the effect elicited by a drug is its raison d’etre, drug action and
`effect will be discussed first in the text that follows, even
`though they are preceded by other events.
`
`METAB0l_lTES ~-.\\
`l
`‘\,
`SITE OF
`;
`BloTRANsFoRMATiqN
`
`SITEOFADMINISTRATION
`
`Ruorpiion
`
`TISSUE .
`DEPOT
`
`F2
`3 CRE‘[|_0,
`
`The absorption, distribution, action, and elimination of a drug
`Fig 37-1
`(arrows represent drug movement).
`Intravenous administration is the
`only process whereby a drug may enter a compartment without passing
`through a‘ biological membrane. Note that drugs excreted in bile and
`saliva may be resorbed.
`'
`'
`
`Drug Action and "Effect
`
`Definitions and Concepts
`
`The word drug imposes an action-effect context within
`which the properties of a substance are described. The de-
`scription must of necessity 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 in a certain
`way, called pain,* to a noxious stimulus. Both because the
`pertinent properties are locked into the complex and.some-
`-what imprecise biological context and because the types of
`possible response are many, descriptions of the properties of
`‘ drugs tend to emphasize the qualitative features of the effects
`they elicit. -Thus adrug may be described as having analgesic,
`vasodepressor, convulsant, antibacterial, etc, properties. The
`specific effect (or use) categories into which the many drugs
`may be placed are the subject of Chapters 40 through 67 and
`will not be elaborated upon in this chapter.‘ However, the
`description of a drug does not end with the enumeration of the
`responses it may elicit. There are certain intrinsic properties
`of the drug—recipient system that-can be described in quan-
`titative terms and which are essential to the full description
`' of the drug and to the validation of the drug for specific uses.
`Under Definitions and Concepts, below, certain general terms
`are defined in qualitative language; under Dos'e—Effect Re-
`lationships the foundation is laid for an appreciation of some
`of the quantitative aspects‘ of pharmacodynamics.
`
`* Sophisticated studies indicate that pain is noifsimply the perception
`of a certain kind of stimulus but rather a reaction to the perception of a
`variety of kinds of stimuli or stimulus patterns.
`-
`
`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 are important to the‘ proper
`understanding of pharmacology. It is necessary to differen-
`tiate among action, effect, selectivity, dose, potency, and ef-
`ficacy.
`-
`‘
`Action vs Effect—‘—-The effect of a drug is an alteration of
`function of the 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
`condition that brings about the effect.
`’
`The final effect of adrug may be far removed from its site
`of action. For example, the diuresis subsequent to the in-
`gestion of ethanol does not result from an action on the kidney
`but instead from a depression of activity in the supraopti-
`cohypophyseal region of the hypothalamus, which regulates
`the release of antidiuretic hormone from the posterior pitu-
`itary gland. The alteration‘ of supraopticohypophyseal
`function is, of course, also an effect of the drug, as is each
`subsequent change in the chain of events leading’to diuresis.
`The action 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 exerting
`a single effect, although a number are _known that appear to
`have .a single mechanism of action.
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`714
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`CHAPTER 37
`
`determined by the ‘pattern of distribution of destructive or
`derive from a single mechanism of action. For example, the
`activating enzymes among the tissues and by other factors.
`inhibition of acetylcholinesté,ras.e“by physostigmine will elicit
`Dose—Even the uninitiated person knows that the dose
`an effect at every site where acetylcholine is produced, is po-
`of a drug is the amount administered. However, the appro-
`tentially active, and is hydrolyzed by cholinesterase. Thus
`priate dose of a drugis not some unvarying quantity, a fact
`physostigmine elicits a constellation of effects. .
`.
`.
`A drug can also cause multiple effects at several different‘
`sometimes overlooked by pharmacists, official committees,
`and physicians, and the practice of pharmacy is entrapped in
`.sites by a single action at only one site, providing that the
`a system of fixed~dose formulations, so that fine adjustments
`function initially altered at the site of action ramifies to con-
`in dosage are often difficult to achieve. Fortunately, there
`trol other functions -at distant sites. Thus a drug that sup-
`is usually a rather wide latitude allowable in dosages.
`It is
`presses steroid synthesis in the liver may not only lower serum
`obvious that the size of the recipient individual should have
`cholesterol, iinpairnerve myelination and function, and alter
`a bearing upon the dose,_ and the physician may elect to
`. the condition of the skin (as a consequence of cholesterol de-
`administer the drug on a body—weight basis rather than as a
`ficiency) but also may affect digestive functions (because of
`fixed dose. ~.Usually, however, a fixed dose is given to all
`a deficiency in bile acids) and alter adrenocortical and sexual
`adults, unless the adult is exceptionally large or small. The
`hormonal balance.
`dose for infants and children is often determined by one of
`Although a single action’ can give rise to multiple effects,
`several formulas which take into account’ age or weight, de-
`most drugs exert multiple actions. The various actions may
`pending on the age group of the child and the type of action
`be related, as, for.example,' the sympathomimetic effects of
`exerted by the drug.
`Infants are relatively more sensitive to
`metaraminol that accrue to itsstructural similarity to nor-
`many drugs, often because enzyme systems which destroy the
`epinephrine and its ability partially to suppress sympathetic
`drugs may not be fully developed in the infant.
`'
`responses -because it occupies the catecholamine storage pools
`The nutritional condition of the patient, the mental outlook,
`in lieu of norepinephrine;‘ or the actions may be unrelated, as
`the presence of pain or discomfort, the severity of the condi-
`with the actions of morphine to interfere with the release of
`tion being treated, the presence-of secondary disease or pa-
`acetylcholine from certain autonomic nerves, to block some
`thology, genetic, and many other factors affect the dose of ‘a
`actions of 5—hydroxytryptamine (serotonin), and to release
`drug necessary to achieve a given therapeutic response or to
`histamine.
`.Many' drugs bring, about immunologic (allergic
`cause an untoward effect (Chapter 69). Even two appar-
`or hypersensitivity) responses’ that bear no relation to the
`ently well-matched normal persons may require widely dif-
`other pharmacodynamic actions of the drug.
`ferent doses for the same intensity of effect. Furthermore,
`Selectivity——Despite the potential most drugs have for
`a drug is not always employed for the same effect and hence
`eliciting multiple effects, one effect is generally more readily
`not in the same dose. For example, the dose of a progestin
`elicitable than another. This differential responsiveness is
`necessary for an oral contraceptive effect is considerably
`called selectivity.
`It is usually considered to be a property
`different from that necessary to prevent spontaneous abor-
`of the drug,.but it is also a property of the constitution and
`tion, and a dose of an estrogen for the treatment of the men-
`biodynamics of the recipient subject _or patient.
`..
`;
`opause is much too small for the treatment of prostatic car-
`. Selectivity may come about in several ways. The subcel-
`cinoma.
`lular structure (receptor) with which a drug combines to ini-
`From the above it is evident that the wise physician knows
`tiate one response may have a higher affinity for the drug than
`that the dose of a drug is "enough” (ie, no rigid quantity but
`that for some other action; atropine, for example, has a much.
`rather that which is necessary and can be tolerated) and in-
`higher affinity for muscarinic receptors (page 876) that sub-
`dividualizes his regimen accordingly. The wise pharmacist
`serve the function of sweating than it does for the nicotinic
`will also appreciate this dictum and recognize that official or
`receptors (page 876) that subserve voluntary neuromuscular
`manufacturer’s recommended doses are sometimes quite
`transmission, so that suppression of sweating can be achieved
`narrowly defined and may be very wideof the mark. They I
`with only a tiny fraction of the dose necessary to cause pa-
`should serve only as a useful guide rather than as an=impera-
`ralysis of the skeletal muscles. A drug may be distributed
`tive. .
`,
`:
`v
`--
`_
`-
`xv"
`._
`unevenly, so that it reaches a higher concentration at one site
`Potency and Efficacy—:-The potency of a drug is the re-
`than generally througlloutthe tissues; chloroquineis much
`ciprocal of dose. , Thus it will have the units of persons/unit
`more effective against hepatic than intestinal (colonic) ame-
`weight of drug or body weight/unit weight of drug, etc. Po,-
`biasisbecause it reaches a many times higher concentration’
`tency generally haslittle utility other thanto providea means
`in the liver than in the wall of the colon. An affected function
`of comparing the relative activities of drugs in a series, in
`may be much more critical to or have less reserve in one organ
`which case relative potency, relative to some prototype
`than in another, so that a drug will be predisposed to elicit an
`member of the series, is a parameter commonly used amon
`effect at the more critical site; some inhibitors of dopa de-
`pharmacologists and in the pharmaceutical industry. =
`.
`carboxylase (which is also 5-hydroxytryptophan decarbox-
`' Whether, a given drug is more.potent than another has little
`ylase) depress the synthesis of histamine more than that of
`bearing .on its clinical usefulness,,provided that the potency .
`either norepinephrine or 5-hydroxytryptamine (serotonin),
`.is»not so low that the size of the dose is physically unman
`even though histidine decarboxylase is less sensitive to the
`ageable or the cost of treatment is higher than withan
`drug, simply because histidine decarboxylase is the only. step
`equivalent drug.
`If a drug is less potent but more select
`and hence is rate-limiting in the biosynthesis of histamine.
`then-it is the one to be preferred. Promotional arguments ,'_
`Dopa decarboxylase is not rate-limiting in the synthesis of
`favor of a more potent drug are, thus irrelevant to the impoi‘
`either norepinephrine or. 5—hydroxytryptamine until the en-
`tant considerations that should govern the choice of a dr
`zyme is nearly completely inhibited. Another example of the
`However, it sometimes occurs thatidrugs of the same cl
`determination of selectivity by the critical balance of the af-
`differ in the maximum intensity of effect; that is, some dr,_ ,
`fected function is that of the-mercurial diuretic drugs. An
`of the class may be less efficacious than others, irrespectlv
`inhibition of only 1%.in the tubular resorption of glomerular
`of how large a dose is used.
`-
`g
`‘
`filtrate will usually double urine flow, since 99% of the glo-
`Efficacy connotes the property of~a drug to achieve,
`merular filtrate is normally resorbed; aside from the question
`desired response, and maximum efficacy denotesthe In
`of the possible concentration of diuretics in the urine, a
`mum achievable effect. Even huge doses of code_i1}e Of
`drug-induced reduction of 1% in sulfhydryl enzyme activity
`cannot achieve the relief from severe pain that relati_v?e1YI
`in tissues other than the kidney is not usually accompanied
`doses of morphine can; thus codeine is said to have a?10
`byan observable change in function. Selectivity also can be
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`maximum efficacy t,han’morphiiie. u:_'Efficacy is one of the
`primary determinants of the choice of a drug.
`Dose—Effect Relationships
`Thevimportance of knowing how changes in the intensity
`of response to a drug vary with the dose is virtually self-evil
`dent. Both the physician, who prescribes or administers a
`drug, and the manufacturer, who must package the drug in
`'
`'
`izes, must translate such knowledge into
`heoretical or molecular pharmacologists
`nships in inquiries into mechanism of
`action and receptor theory (see page 718). It is necessary to
`define two types of relationship: . (1) the dose—intensity re-t
`lationship—-ie, the manner in which the intensity of effect
`in the individual recipient relates to dose——and (2) dose—fre-
`—-ie, the manner in which the number
`_ ng a population of recipients relates to
`
`\v\._/',?DEQ)o(D'aV(D-?n‘:.
`
`555
`
`.20‘
`
`_
`
`. 40
`30» .-
`r
`DOSE (mcg/Kg)
`.
`.‘
`The relationship of the-intensity of the blood-pressure re-
`V Fig 37-2.
`sponse of the cat to the Intravenous dose of levarterenoi. '
`
`“5o'
`
`-60
`
`l7o‘
`
`e of the abscissa, the smallest-
`being 1.5 X 1O‘3 ,ug. Actually, the x intercept has a
`positive value, since a finite dose of drug is required to bring
`
`set of data.
`Because the dose range may be 100 _or i000 fold fromthe
`lowestito the highestdose, it has become the practicetoplot
`hmic scale of abscissa
`
`ft) or in relative units, as -pe,rcent.(at the
`right).
`.
`"
`Q ,
`-
`a
`-
`v
`‘Although no new information is created by a semi1oga-
`rithmicrepresentation, the curve is stretched out in such a way
`as to facilitate the inspection of the data; the comparison of
`results from multiple observations and the testing of different
`drugs is also rendered easier. Iln the example shown, the curve
`is.essentially what is called a sigmoid curve and '
`symmetrical about the point which represents an '
`
`9)‘
`
`73. The relationship of the intensity of
`lood-pressure response of the cat to the
`e intravenous dose of ievarterenol.
`
`iPRESS__URE(mmHmO:3oo_0
`
`
`INCREASElN.BLOOD8
`
`‘O7
`
`0
`
`3 cr
`
`
`
`PERcamor-‘MAXIMUMEFFE
`
`TI;/A’ PHl°.l§i\(l‘lAii§’I§.EJ(?l"R§i.4iL9é’iiEi‘Sil¢l,
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`716
`
`CHAPTER 37
`
`equal to 50% of the maximal, effect, iefabout the mid-point.
`The symmetry follows from the rectangular -N hyperbolic
`character of the previous Cartesian plot (Fig 37-2). The
`semilogarithmic plot reveals better the dose—effect relation-
`ships in the low-dose range, which are lost in the steep slope
`of the Cartesian plot. Furthermore, the -data about the
`mid-point are almost a straight line; the nearly linear portion
`covers approximately 50% of the curve. The slope of the
`“linear” portion of the curve, or, more correctly, the slope at
`the point of inflection, has theoretical significance (see ‘Drug
`Receptors and Receptor Theory, page 718).
`'
`’
`The upper portion of the curve approaches an asymptote,
`which is the same as that in the Cartesian plot.
`If the re-
`sponse system is completely at rest before the drug is ad-
`ministered, the lower portion of the curve should be asymp-
`totic to the x axis. Both asymptotes-and the symmetry derive
`from the law of mass action (see page 719).
`“
`Dose—intensity curves often deviate from the ideal config-
`uration illustrated and discussed above. Usually, the deviate
`curve remains sigmoid but not extended symmetrically about
`the mid-point of the “linear” segment. Occasionally other
`shapes occur, sometimes quite bizarre ones. Deviations may
`derive from multiple-actions’ that convergeupon the same final
`effector system, from Varying degrees of metabolic alteration
`of the drug at different doses, from modulation of the 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 which elicits
`a given ‘intensity of effect. The intensity of effect that is
`generally designated is the 50% of maximum intensity. The
`corresponding dose is called the 50% effective dose, or indi-
`vidual ED50 (see Fig 37-3). The use of the adjective indi-
`vidual distinguishes the ED50 based upon the intensity of
`effect from the median effective dose, also abbreviated ED50,
`determined from frequency of response data in a population
`(see Dose¥Frequency Relationships, this page).
`‘
`Drugs that ‘elicit’ the same quality of effect may be graphi-
`cally compared.
`In Fig - 37-4-, five hypothetical drugs are
`compared.~. Drugs ‘A, B, C, and E "can all achieve the same
`maximum effect, which suggests that the same effector system
`may be common to all. D may possibly be working through
`the same effector system, but there are no a priori reasons to
`think- this is so. Only A and B have parallel curves and
`common slopes‘.
`‘Common slopes-are consistent with but in
`no way. prove, the idea that A and B not only ‘act through the
`same effector system but also by the same mechanism. Al-
`though drug—receptor theory (see Drug’ Receptors and Re-
`ceptor Theory, page 718) requires that the curves of identical
`-mechanism have equal slopes, examples of exceptions are
`known. Furthermore, mass-law statistics require that all
`simple drug-receptor interactions generate the same slope;
`only when slopes depart from this universal slope in accor-
`dance with distinctive characteristics of the response system
`do slopes provide evidence of specific mechanisms.
`'
`‘ The relative potency of any drug may be obtained by di-
`
`viding the ED50 of the standard or prototype drug by that of
`the drug in question. Any level of effect other than'50% may
`be used, but it should be recognized that when the slopes are.
`not parallel, the relative potency depends upon the intensity
`of effect chosen. Thus the potency of A relative to C (in Fig
`37-4) calculated from the ED50 will be smaller than that cal-
`culated from the ED25.
`-
`‘
`*
`The low maximumiintensity inducible by D poses even’
`more complications in the determination of relative potency
`than do’ the unequal slopes‘ of the other drugs.
`If its dose-
`intensity curve is plotted in terms of percent ‘of its own max-
`imum effect,- its relative inefficacy is obscured, and the limi-
`tations of relative potency at the ED50 level will not be evi-
`dent. ‘ This dilemma simply underscoreslthe fact that drugs
`can better be compared from their entire dose—‘intensity
`curves than from a single derived number like ED50 or relative
`potency.
`.
`-
`‘
`«
`~
`.
`-Drugs that elicit multiple effects will generate-a dose—in-
`tensity curve for each effect. Even though the various effects
`may be qualitatively different, the several curves may be
`plotted together on a commonscale of abscissa, and the in-
`tensity may be expressed in terms of percent of maximum
`effect; thus all curves can share a common scale of ordinates
`in additionto,comr'non abscissa.’ Separate scales of ordinates
`could be employed, but would make it harder to compare
`data. ‘
`‘
`
`The selectivity of a drug can be determined by noting what
`percent of maximum of one effect can be achieved before a
`second effect occurs. As with relative potency, selectivity may
`be expressed in terms of the ratio between the ED50 for one
`effect to that for another effect, or a ratio at some other in-
`tensity of effect. Similarly to relative potency, difficulties
`follow from nonparallelismr In such instances, selectivity
`expressed in dose ratios)varies from one intensity level to‘
`another.
`a
`‘
`”
`
`When the doseeintensity curves for a number of subjects
`are compared-,'it is found that they vary considerably from
`individual to individual in many respects;
`threshold dose,
`mid-point, ‘maximum intensity, etc, and sometimes even
`slope. By averaging the intensities of the effect at each dose,
`an average dose—intensity curve can be constructed.
`-
`Average dose-intensity curves enjoya limited application
`in comparing drugs. ‘A.'single line expressingan average re-
`sponse has little value in predicting individual responses un-
`less" it isaccompanied by some expression of the range ofthe
`effect ‘at the various doses. This may be done by indicating
`the standard error‘ of the’ response at each dose. Occasionally,
`a simple scatter diagram is plotted in lieu of an average curve
`and statistical parameters’ (see Fig 10-2, page 106). An av-
`erage dose-intensity curve may also be constructed from a
`population in which different individuals receive different
`doses; if sufficiently large populations are employed, the av-
`erage curves determined by the two methods will approximate
`each other.
`
`INTENSITYOFEFFECT
`
`PERCENTOFMAXIMUM,RESPONSEOFDRUGA
`
`’ Log dose—intensity of effect curves of five different hypo-
`Fig 37-4.
`iheticai drugs (see text for explanation).
`
`It is obvious that the determination of such average curves
`from a population sufficiently large to be statistically mean-
`ingful requires a great deal of work. Retrospective clinical
`data occasionally are treated in this way, but prospective
`studies are infrequently designed in advance to yield average
`curves. The usual practice in comparing drugs is to employ ’
`a quantal (all-or-none) end point and to plot the frequency
`or cumulative frequency of response over the dose range, as
`discussed below.
`Dose—Frequency of Response Relationships-—-When an
`end point is truly all-or-none, such as death, it is an easy
`matter to plot the number of responding individuals (eg, dead
`subjects) at each dose of drug or intoxicant. Many other re-
`sponses that vary in intensity can betreated as all-or-none if
`simply the presence or absence of a response (
`no cough, convulsion or no convulsion, et\r’<l|':)\/E
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`
`‘PERCENTOFANIMALSTHATCONVULSED
`
`
`
`
`
`g
`
`i/En so =322 mg/Kg
`
`DRUG ABSORPTION, ACTION, AND DISPOSITION
`
`717
`
`first derivative of the dose—cumulative frequency curve and
`is a frequency—distribution curve (see Chapter 10). The
`distribution will be symmetrical—ie, normal or Gaussian (see
`Fig 10-6, page 109)——only if the dose—cumulative frequency
`curve is symmetrically hyperbolic. Because most dose—
`cumulative frequency curves are more nearly symmetrical
`when plotted semilogarithmically (ie, as_ log dose), dose-
`cumulative frequency curves are usually log-normal. v
`e
`'
`Since the dose—intensity and dose—cumulative frequency
`curves are basically similar in shape, it follows that the curves
`have similar defining characteristics, such as ED50, maximum
`effect (maximum efficacy), and slope.
`In,dose—cumu.lative
`frequency data, the ED50 (median effective dose) is the dose
`to which 50% of the population responds (see Fig 37-5).‘ If
`the frequency distribution is normal, the ED50 is both the
`arithmetic mean and median dose and is represented by the
`mid-point on the curve; if the distribution is log-normal, the .
`ED50 is the medianidose but not the arithmetic mean dose.
`The efficacy is-the cumulative frequency summed over all
`doses; it is usually but not-always 100%. The slope is char-
`acteristic of both the drug and test population. Even two
`drugs of identical mechanism may give rise to different slopes
`in dose-percent curves, whereas in d0se—intensity curves the
`slopes are the same.
`‘
`Statistical parameters (such as standard deviation)———‘in
`addition to ED50, maximum cumulative frequency (efficacy),
`the slope——characterize dose-cumulative frequency rela-
`tionships~(see Chapter 10).
`-
`There are several formulations for dose-cumulative fre-
`quency curves, some of which are employed only to define the
`linear segment of a curve and to .determine_ the statistical
`parameters of this segment. For the statistical treatment of
`dose—frequency data, see Chapter 10. Onesimple mathe-
`matical expression of the entire log-symmetrical sigmoid curve
`IS
`~
`-
`A
`
`,
`
`L9
`l.7
`.I.e ,
`,
`-1.5
`V
`A
`_
`LOG‘ DOSE (log mg/Kg)
`‘
`Fig 37-5.‘ The relationship of the number of responders in a population
`of mice‘ to the dose of pentyienetetrazol (courtesy, Drs DG McQuarry
`:and EG Fingl, University of Utah).
`
`I.8
`
`‘
`
`;
`
`= without regard to theintensity of the ‘response when it oc-
`urs.
`»
`.
`.
`~ n
`When the response grades from the basal or control state
`a less abrupt manner ‘(eg, tachycardia, miosis, rate of
`as
`'c secretion, etc), it may be necessary to designate arbi-
`.,
`ily some particular intensity of effect astheend point.
`If
`he nd point is taken as an increase in heart rate of 20 '
`ts/min,’ then all individuals whose tachycardia is less than
`would be recorded as nonresponders, while all those
`L 20 or abovewould be recorded as responders.
`.When the
`cent of responders in the population is plotted against the
`e, a characteristic dose—response curs/"e,‘more properly
`I a d0se—cumulative frequency or d0se—percent curve,
`enerated. Such a "curve is, in fact, a cumulative,fre-
`I
`"
`distribution curve, the percentlof responders at a
`dose being the frequency of response. ,
`.,
`.
`'
`e—cumulative frequency curves are generally of the same
`tric shape as dose—intensity curves (namely, sigmoid)
`V equency is ‘plotted against log dose (see Fig 37-5).
`endency of the cumulated frequencyof response (ie,
`13) to be linearly proportional to the log of the dose in
`die of the dose range is called the Weber-Fechner law,
`itis not invariable, as a true natural law should be.‘
`instances, the cumulative frequency is simply pro-.
`I}a1»to dose rather than log dose. The Weber—Fechner
`P11 * to either dose—intensity or dose—cumulative fre-
`‘ata. The similarity between dose—frequenc_y« and
`sity.curves may be more than fortuitous, sincethe
`_ response will usually have an approximately linear
`Y’ D to’ the percent of responding units (smooth
`_,lls, nerve fibers, etc) and hence is also a type of cu-
`frequency of response. These are the same kind of
`that govern the law of mass action.
`’
`'
`the increase in the number of responders with each
`13 Plotted, instead of the cumulative percent of re-
`? bellshaped curve is obtained. This curve is the
`
`_
`
`'
`
`% response
`
`_
`
`(1)
`‘log .d0Se - K +flog i100% - response)
`where percentresponse may be either the percentof maxi-
`mum intensity -or the percent of a population responding.
`Theequation is thus basically the same for both log normal
`dose—intensi_ty and :log normal dose—percent relationships. . K
`is a constant that is characteristic of the mid-point of the
`curve, or ED50, and 1/f is characteristically related to the slope
`of the linear segment, which, in turn is closely related to the
`standard deviation of the derivative log normal frequency
`distribution curve.
`,
`The comparison of dose—percent relationships among drugs
`is subject -to the pitfalls indicated for dose—intensity com-
`parisons (seepage 715),’ namely, that when the slopes of the
`‘curves are not the same (ie, the dose~percent curves are not
`parallel),' it is necessary to state at which level of response a
`potency ratio is calculated. As with dose—intensity data,
`potencies are generally calculated-from the ED50, but potency
`ratios may be calculated for any arbitrary percent response.
`The expression of selectivity is likewise subject to similar.
`qualifications‘, inasmuch as the dose~percent curves for the
`several effects are usually nonparallel.
`‘
`‘
`The term therapeutic index is used to designate a quanti-
`tative statement of the selectivity of adrug when a therapeutic
`and an untoward effect are being compared.‘ -If the untoward
`effect is designated as T (for toxic) and the therapeutic effect
`as E, the therapeutic index may be defined as TD50/ED50 or"
`a similar ratio at some other arbitrary levels of response. The
`TD and the ED are not required to express the same percent
`of response; some ‘clinicians use the ratio TD1/ED99 or ‘
`TD5/ED95, based. on the rationale that if the untoward effect '
`is serious, it is important to use a most se
`el
`ic030
`index in passing judgment u on the
`y,L|_C
`a
`TEVA PHARMAC UTICAL USA.|
`
`RBP_TEVA05017800
`
`TEVA EXHIBIT 1030
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`718
`
`CHAPTER 37
`
`p,”
`
`therapeutic indices are known in -manifor only a few drugs. -
`There will be'a different therapeutic index for each un-‘
`toward effect that a drug may elicit, and, if there is more than
`one therapeutic effect, -a family of therapeutic indices for each
`therapeutic effect.‘ However, in clinical practice, it is cus-
`tomary to ‘distinguish among the various toxicities by indi-
`cating the percent incidence of a given side effect.
`Variations in Response and Responsiveness—From the
`above discussion of dose—frequency relationships and Chapter
`10, it is obvious thatin a normal population of persons there
`maybe quite a large difference in the dose required to elicit
`a‘ given response in the least-responsive member of the pop"-
`ulation and that to elicit the response inithe most~responsive
`member. The difference will ordinarily be a function of the
`slope of the dose—percent curve, or, in statistical terms, of the
`standard deviation. ‘ If the standard deviation is large,—the
`extremes of responsiveness of responders -are likewise -large.‘
`In a normal population 95.46% of the population responds
`to doses within two standard deviations from the -ED50 and
`99.73% within three standard deviations.
`In log normal
`populations the same distribution applies when standard
`deviationfis expressed as log dose.
`-
`" '
`‘
`In the population represented in Fig 37-5, 2.25% of the
`population (two standard deviations from the median) would
`require a dose more than 1.4 times the ED50; an equally small
`percent would -respond to 0.7 the ED50.' ‘The physician who
`is unfamiliar with statisticsis aptto consider the 2.25% at ei-
`ther extreme as abnormal reactors. The statisticianlwill argue
`that these 4.5% are within the normal population and that only
`those who respond well outside of the normal population, at
`least three standard deviations from the median,'deserve to
`be called abnormal.
`‘
`'
`Irrespective of whether the physician’s or the statistician’s
`criteria of abnormality obtain, the term hyporeactive applies
`to those individuals who require abnormally high doses and
`hyperreactive to those who require abnormally low doses.
`The terms hyporesponsive and hyperresponsive may also be
`used.
`It is incorrect to use the terms hyposensitive and hy-
`persensitive in this context; hyper