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`· · · . ·· · Remington's
`Pharmaceutical
`Sciences
`
`17
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`DRL - EXHIBIT 1030
`DRL001
`
`

`
`17rn
`
`EDITION
`
`·Remington's
`
`ALFONSO R GENNARO
`Editor, and Chairman
`of the Editorial Boord
`
`DRL - EXHIBIT 1030
`DRL002
`
`

`
`--------------------~~~.
`II A ·w1AJNa · tJ~c:f( Qvtr.s ,
`WINS II
`
`-
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`/JNJJ
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`rx. u11Tell
`
`Pharmaceutical
`
`..
`
`Sciences
`
`I
`1·
`
`I
`
`1985
`
`MACK PUBLISHING COPMANY
`
`Easton, Pennsylvania 18042
`
`DRL - EXHIBIT 1030
`DRL003
`
`

`
`CHAPTER 37
`
`Drug Absorption, Action, and Dispositi.on
`
`Stewart C Harvey, PhD
`.
`· Prorusor of Pharmocology
`School of Modlcln•. Unl~erslry of Utah
`Salt Lok• City, UT 84132 .
`
`AJthough drugs differ widely in. their pharmacodynamic
`effects and clinical application, in penetiance, 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(cid:173)
`!!zed to inactive or active products, or excreted. The history
`of a drug in the body is summarized in Fig 37-1. Each of the
`process~s or events depicted rela~s impor~ntly to . thera(cid:173)
`peutic and toxic effects of a drug and to the mode of admin(cid:173)
`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 llvents.
`
`z
`2
`
`TISSUE
`DEPOT
`
`URINE
`
`Fig 37-1. The absorption, distribution, action, and elimination of a drug
`(arrov.s represent drug movement).
`Intravenous administration Is the
`only process whereby a drug may enter a compartment without passing
`through a blologlcal 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 subs.tance are described. The de(cid:173)
`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(cid:173)
`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 a drug 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 enumerati9n of the
`responses it may elicit. There are certain intrinsic properties
`of the drug- recipient system that·can be described in quan(cid:173)
`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 Dose-Effect Re(cid:173)
`lationships the foundation is laid for an appreciation of some
`of the quantitntive ARpP.ctA of pharmacodynamic.s.
`
`,•
`. • Sophisticated studies indicate that pain is nofsimply the perception
`of a certain'kind of stimulus but rather a reaction to th'e perception of a
`'votiety 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
`unde1standing of pharmacolo.gy. It is necessary to diUeren(cid:173)
`tiate among action, effect, selectivity, dose, potency, and ef(cid:173)
`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 a drug may be far removed from its site
`of action. For example, the diuresis subsequent to the in(cid:173)
`gestion of ethanol does not result from an action on the kidney
`but instead from a depression of activity in the supraopti(cid:173)
`cohypo"physeal ·region of tl)e hypothalamus, which regulates
`the release of antidiuretic hormone from the posterior pitu(cid:173)
`itary gland. The alteration· of supraopticohypophyseal
`function is, of course, also ari effect of the drug, as is each
`subsequent change in the chain of eve~ts le~dingto diuresis.
`The action of ethnnol was exerted only.at the initial step, each
`subsequent effect being then the action to a following step.
`· Multiple E ffects--No known drug is capable of exerting
`a single effect, although a number are .known that appear to
`have a single mechanism of action. Multiple effects may
`T
`713
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`DRL - EXHIBIT 1030
`DRL004
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`

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`714
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`CHAPTER 37
`
`derive from a single ~echanisip of acti.on. Fo.r example, the
`inhibition of acetylcholinesteras.e·by physostigmine will elicit
`an effect at every site where acetylcholine is produced, is po(cid:173)
`tentially active, and is hydrolyzed by cholinesterase. Thus
`physostigmine elicits a constellation of effects.
`.
`.
`A drug can also cause multiple effects at several different
`.sites by a single action at only ·one site, providing 'that the
`function initially altered at the site of action ramifies to con(cid:173)
`trol other functions at distant sites. Thus a di-ug that sup(cid:173)
`presses steroid synthesis in the liver may not only lower serum
`cholesterol, impair nerve myelination and function, and alter
`the condition of the skin (as a consequence of cholesterol de(cid:173)
`ficiency) but also may affect digestive functions (because of
`a deficiency in bile acids) and alter adrenocortical and sexual
`hormonal balance.
`Although a single action can give rise to multiple effects,
`most drugs exert multiple actions. The various actions may
`be related, as, for example, the sympathomimetic effects of
`metaraminol that accrue to its.structural similarity to nor(cid:173)
`epinephrine and its ability partially to suppress sympathetic
`responses because it occupies the cntecholamine storage pools
`iii lieu of norepinephrine; or the actions may tie umelated, as
`with the actions of morphirfe to interfere with the release of
`acetylcholine from certain autonomii; nerves, to block some
`actions of 5-hydroxytryptamine (serotonin), and to release
`histamine. Many drugs bring about immunologic (allergic
`or hypersensitivity) responses' that bear no relation to ~he
`othe;r p~armacodynamic actions of the drug.
`Selectivity- Despite the potential most drugs have for
`eliciting multiple effects, one effect is generally more readily
`elicitable than another. This differential responsiveness is
`called selectivity. It is usually considered to be a property
`of the drug, but it is also a prope1·ty of the constitution and
`biodynamics of the recipient subject or patient. ..
`:
`. Selectivity may come about in several ways. The subcel(cid:173)
`lular structure (rec~ptor) with which a drug combines to ini(cid:173)
`tiate one response may have a higher affinity for the drug than
`that for some other action; atropine, for example, has a much
`higher affinity for muscarinic receptors {page 876) that sub(cid:173)
`serve the function of sweating than it does for the nicotinic
`receptors (page 876) that subserve voluntary neuromuscular
`transmission, so that suppression of sweating can be achieved
`with only a tiny fraction of the d9se necessary to cause pa(cid:173)
`'A drug may be distributed
`ralysis of the skeletal muscles.
`unevenly, so that it reaches a higher concentration at one site
`than generally throughout'the tissues; chloroquine.is much
`more effective against hepatic than intestinal (colonic) ame(cid:173)
`biasis. because it reaches a many times higher concentration·
`in the liver than in the wall of the colon. An affected function
`may be much more critical to or have less reserve in one organ
`than in another, so that a drug will be predisposed to elicit an
`effect at the more critical site; some inhibitors of dopa de(cid:173)
`carboxylase (whil'.:h is also 5-hydroxytryptophan decarbox(cid:173)
`ylase) depress the synthi:sis of histamine more than that of
`either norepinephrine or 5-hydroxytryptamine (serotoni~),
`even though histidine decarboxylase is less sensitive to the
`drug, simply because histidine .decarboxylase is the only step
`and hence is rate-limiting in the biosynthesis of histamine.
`Dopa decarboxylase is not rate-limiting in the synthesis of
`either norepinephrine or 5-hydroxytryptamine un.til the en(cid:173)
`zyme is nearly completely inhibited. Another example of the
`determination qf selectivity by the critical balance of the af(cid:173)
`fected function is that of the mercurial diuretic drugs. An
`inhibition of only 1% in the tubular resorption of glomerular
`filtrate will usually double urine flow, since 99% of the g1o(cid:173)
`merular filtrate is normally resorbed; aside from the question
`of the possible concentration of diuretics in the urine, a
`drug-induced reduction of 1% in sulthydryl enzyme activity
`in tissues other than the kidney is not usually accompanied
`by.an observable change in function. Selectivity also can be
`
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`determined by the pattern of distribution of destructive or
`activating enzymes among the tissues and by other factors.
`Dose- Even the uninitiated person knows that the dose
`of a drug is the amount administered. However, the appro(cid:173)
`priate dose of a drug is not some unvarying quantity, a fact
`sometimes overlooked by pharmacists, official committees,
`and physicians, and the practice of pharmacy is entrapped in
`a system of fixed-dose formulations, so that fine adjus.tmeots
`in dosage are often difficult to achieve. Fortunately, there
`is usually a rather wide latitude allowable in dosages. It is
`obvious that the size of the recipient individual should have
`a bearing upon the dose, and the physician may elect to
`administer the drug on a body-weight basis rather than as a
`fixed dose. .Usually, however, a fixed dose is given to all
`adults, unless the adult is exceptionally large or small. The
`dose for infants and children is often determined by one of
`several formulas which take into acco'unt age or weight, de(cid:173)
`pending on the age group of the child and the type of action
`exerted by the drug. Infants are relatively more sensitive to
`many drugs, often because enzyme systems which destroy the
`drugs may not be fully developed in the infant.
`The nutritional condition of the patient, the mental outlook,
`the presence of pain or discomfort, the severity of the condi(cid:173)
`tion being treated, the presence of secondary cfouiase or pa(cid:173)
`thology, genetic, and many other factol's affect the dose of a
`drug necessary to achieve a give1i therapeutic response or to
`cause an untoward effect (Chapter 69). Even two appar(cid:173)
`ently well-matched normal persons may require widely dif(cid:173)
`ferent doses for the same intensity of effect. Furthermore,
`a drug is not. always employed for the same effect and hence
`not in the same dose. For example, the dose of a progestin
`necessary for an oral contraceptive effect is considerably
`different from that necessary to prevent spontaneous abor(cid:173)
`tion, and a dose of an estrogen for the treatment of the men(cid:173)
`opause is much too small for the treatment of prostatic car(cid:173)
`cinoma.
`From the above it is evident that the wise physician knows
`that the dose of a drug is "enough" (ie, no rigid quantity but
`. rather that which is necessary and can be tolerated) and in(cid:173)
`dividualizes his regimen accordingly. The wise pharmacist
`will also appreciate this dictum and recognize that official or
`manufacturer's recommended doses are sometimes quite
`narrowly defined and ~ay be very wide of the mark. They
`should serve only as a useful-guide rather than as an'impera-
`tive,
`:
`P oten cy and Efficacy-The poten.cy of a drug is the re(cid:173)
`ciprocal of dose .. Tl:ius it will have the ul)its of persons/µnit
`weight of drug or body weight/unit weight of drug, etc. ~9.­
`tency generally has little utility other than to provide a means
`of comparing the relative activities of drugs .in a serieii. in
`which case relative potency, relative to .some pr.ototype
`member of the series, is a parameter commonly used .among
`pharmacologists 81\d in the pharmaceutical industry. ,
`Whether a given drug is more potent than another h!IS little
`bearing on its clin\cal usefulness, provided that the potency
`js not so low that the size of the dose is physically unman(cid:173)
`ageable or the cost of treatment is higher than with an
`equivalent drug. If a drug is less potent but more selective,
`then it is the one to be preferred. Promotional argument.sin
`favor of a more potent dfug are. thus irrelevant to the impor(cid:173)
`tant considerations that should govern the choice of a drug.
`However, it sometimes occurs that chugs of the same class
`differ in the maximum intensity of effect; that is, some drugs
`of the class may be less efficacious .than others, irrespective
`of how large a dose is used.
`·
`. ·.
`Efficacy connotes the property of·a drug to achieve t~e
`desired response, and maximum ef f ica.cy denotes th~ maxi(cid:173)
`mum achievable effect. Even huge doses of cod~ine often
`
`cannot achieve the relief from severe pairi that rela~iJ~ly small J
`
`doses of morphine can; thus codeine is said to. have a lower
`
`-
`
`DRL - EXHIBIT 1030
`DRL005
`
`

`
`~---------------... ---
`
`DRUG ABSORPTION, ACTION, AND DISPOSITION
`
`71'5
`
`.
`.
`...,,,.. y- osymplol~ • moxlmum effecl • efficacy
`······'-'·························· .. ··· : ........................ .
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`~120
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`0
`
`. 10 .
`
`30· . 40
`DOSE (mcg/Kg)
`Fig 37-2. The relationship of the·intenslly of the blood-pressure re(cid:173)
`sponse of the cat to the intravenous dose of levarterenol. ·
`.
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`maximum effic;cy the,n :morphih~. :'Efficacy is one of the
`primary determinanls o~ the choice of a drug.
`
`Dose-Effect Relationships
`.
`•:
`The importance of k.nowing how changes in the intensity
`of response to a drug vary with the dose is virtually self-evi(cid:173)
`C{ent. Both the physician, who prescribes or administers a
`drug, and the manufacturer, who must package the drug in
`appropriate dose sizes, must translate such knowledge into
`everyday practicjl. Theoretical or molecular pharmacologists
`also.study such relationships in inquiries into mechanism of
`action and receptQr theory (see page 718). It is necessary to
`define two types of relationship: (1) the dose- intensity re-·
`lationship-ie, the manner in which the ·intensity of effect
`in the individual recipient relates to dose-and (2) dose-fre(cid:173)
`quency 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 vivo (eg, the blood(cid:173)
`pressure response to epinephrine. in the human patient) or in
`vitro .(eg, the response of the isolated guinea pig ileum to
`hi.stawine), the dose- intensity of e{fect (often called dose(cid:173)
`effect) curve usually has a characteristic shape, namely a curve
`that closely resembles one quadrant of a rectangular hyper-
`.. ..
`bola.
`In ~he dose- intensity curve depicted in Fig 37-2, the curve
`appears to intercept the x axis at 0 only because the lower
`d0$es are quite small on the scale of the abscissa, 'the smallest·
`dose being 1.5 X 10-3 µg. Actually, the x intercept has a
`positive value, since a finite dose of drug is required to bring
`about a r~sponse, this lowest effective dose being known as the,
`threshold dose. Statistics and chemical kinetics predict that
`the curve should approach they axis asymptotically. How(cid:173)
`ever, if the intensity of the measured variable does·not start
`from zero, the curve may possibly have a positive y intercept
`(or negative x intercept), especially if the ongoing basal ac(cid:173)
`tivity befoi:e the drug is given is closely related to that induced
`by the drug.
`.
`In practice, instead of an asymptote to .the y ·axis, dose(cid:173)
`intensity curves nearly always show an upward c~mcave foot
`at the .9rigin of the curve, so that the curve has a lopsided
`sigmoid shape. At high doses the.curve approaches an as(cid:173)
`ymptote which is parallel to the·x axis, and the value of the
`asymptote establishes-the maximum possible'l'esponse to the .
`drug, or.maximum efficacy. However, experimental data in
`
`! ••
`
`Fig 37 -3. The relatlonshlp of the Intensity of
`the blOOd-pressure response of the cat to the
`log of the Intravenous dose of levartereriol.
`
`9
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`the regions of the asymptotes are generally too en-atic to
`permit an exact definition of the' curve at the very low and very
`high doses. The example shown represents an unusually good
`set bf data.
`Because the dose range may be 100 or 1000 fold from the
`lowesno the highest.dose, it has become the practice to plot
`dos~intensity curves on a logarithmic scale of abscissa; ie,
`to plot the log of dose vs the intensity of effect. Fig 37-3 js ·
`such.a semilogarithmic plot of the same data as in Fig 37-2.
`In the figure the intensity of effect is plotted both in absolute
`units (at the ·left) or in relative units, as ·p~rcent. (at the
`.
`ri~rj.
`Although no new information ·is created by a semiloga(cid:173)
`rithmic representation, the cw-ve 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 differept
`drugs is also rendered easier. ·.In the example show.n, the curve
`is.essentially what is called a sigm-0id curve and is nearly .
`syinmeti:ical about tlie point which represents ap intensity
`
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`0
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`LO<? OOSE (log m9/k9)
`
`DRL - EXHIBIT 1030
`DRL006
`
`

`
`718
`
`CHAPTER 37
`
`.... .
`
`).
`
`equal to 50% of the maximal. effect, ie, 1about the mid-point.
`The symmetry follows from the rectangular. hyp·erbolic
`character of the previous Ca.rtesian plot (Fig 37-2). The
`semilogarithmic plot reveals better the dose-effect relation(cid:173)
`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(cid:173)
`sponse system is completely at rest before the drug is ad(cid:173)
`ministered, the lower portion of the curve should be asymp(cid:173)
`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(cid:173)
`ur..ition illustrated and discussed above. Usually, the deviate
`curve remains sigmoid but not .extended symmetrically about
`the mid-point of the "lineat" segment. Occasionally other
`shapes occur, sometimes quite bizarre ones. Deviations may
`derive from multiple actions that converge'i_1pori the same rmal
`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 5d% effective dose, or indi(cid:173)
`vidual ED50 (see Fig 37-3). The use of the adjective in{li(cid:173)
`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(cid:173)
`In Fig 37-4, fi\le hypothetical drugs are
`cally compared.
`compared. Drugs A, B, C, ·and E can all achieve the same
`m~imum effect, which suggests that the same effector system
`may he common to all. D may possibly be working through
`the same effector system, but there are no a priori reasons to
`think•tl1is 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(cid:173)
`t.hough drug-receptor theory (see Drug Receptors and Re(cid:173)
`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(cid:173)
`dance with distinctive characterjstics of the response system
`do slopes provide evidence of specific mechanisms.
`·
`The relative potency of any drug may be obtained by di-
`
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`26
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`LOG DOSE
`Fig 37-4. · Log dose-Intensity of effect curves of five different hypo(cid:173)
`thetical drugs (see text for explanation).
`
`0
`
`viding the ED50 of the standard or prototype drug by that of
`the drug in questioJ1. 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 intetlsity
`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(cid:173)
`culated from the ED25.
`The low maximum' intensity 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(cid:173)
`intensity curve is plotted in terms of percent of its own max(cid:173)
`imum effect,· its relative inefficacy is obscw·ed, and the limi(cid:173)
`tations of relative potency at the ED50 level will not be evi(cid:173)
`dent. This dilemma simply underscores the fact that drugs
`can better be comparetl ·from their entire dose- intensity
`curves than from a single derived number like ED50 or relative
`potency.
`Drugs that elicit nittltiple effects will generate a dose- in(cid:173)
`tensity curve for each effect. Even thoµgh the various effects
`may be qualitatively different, the several curves· may be
`plotted together on a common scale of abscissa, and the in(cid:173)
`tensity may be expressed in terms of percent of maximum
`effoct; thus an ·curves cai1 shiue a con'l.mon scale of ordinates
`in addition to.common abscissa. Separate scales of ordinates
`coutd be employed, but would make it harder to compare
`.
`~~ ·
`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(cid:173)
`tensity of effect. Similarly to relative potency, difficulties
`folio\\> from nonparallelism~ In such instances, selectivity
`expressed in dose ratios)varies from one intensity level to
`another.
`When the dos~intensity curves for a number of subjects
`are compared·, it is found that they vary considerably from
`individual to individual in many respects: thresh6ld dose,
`mid-point, maximum intensity, etc, and· sometinies even
`slope. By averaging the intensities of the effect at each dose,
`an average dose-intensity .curve can be constructed. ·
`Average dose- intensity curves enjoy.a limited application
`in comparing drugs. · A:single line expressing·an average re(cid:173)
`sponse has little value in predicting individual responses un(cid:173)
`less it is accompanied by some expression of the range of the
`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 liE~u of an average curve
`and statistical parameters· (see Fig 10-2, page 106). An av(cid:173)
`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(cid:173)
`erage curves determined by the two methods will approximate
`each other.
`It is obvious that the determination of such average curves
`from a popula~ion sufficiently large to be statistically mean(cid:173)
`ingful requires a great deal of work. Retrospective clinical
`data occasionally are treated in this way, but prospective
`studies are infrequently designecl in advance to yield average
`curves. The usual pi:actice in comparing drugs is to employ ·
`a quantal (all-or-none) end point and to plot the frequency
`or cumulative frequency of respons!l 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(cid:173)
`sponses that vary in intensity can Qe treated as all-or-none if
`simply the presence or absence of a response (eg, cough or
`no cough, convulsion or no conv~lsion, etc) is recorded,
`
`DRL - EXHIBIT 1030
`DRL007
`
`

`
`" ·
`
`: "\
`
`..
`
`100
`
`90
`
`60
`
`0 w
`VJ
`...J 70
`=> >
`
`' Z
`0
`0
`
`~ x ....
`
`60
`
`VJ
`...J 50
`<l ::.
`z
`<l
`11.
`0
`
`40
`
`0
`
`.... z w 30
`0: w n.
`
`20
`
`~/ED 50 •322 ~/Kg
`
`10
`
`o..,-~_,,,.~__.~~.,..,,_~....,...,,_~,.__~_,_~___.,.
`l2
`1,4
`. 1.5
`'
`1.6 .
`1.7
`1.6
`. 1.9
`LOG. DOSE (109 mg/Kg)
`Fig 37-5: The relationship of the number of responders In a population
`of mice to the dose of pentylenetetrazol (collrte'sy, Ors DG McQuarry
`and EG Flngl, University of Utah).
`
`without regard ~o the-intensity of the response when it oc(cid:173)
`curs.
`When the response grades from the basal or control state
`in a Jess abrupt ~8.Jlner '(eg, tachycardia, miosis, rate of
`gastric &ecretion, etc) it may b& necessary to designate a.rbi(cid:173)
`trarily some particolar intensity of effect as the ·end point. If
`the end ,point is taken as an incre11se in heart i·ate of 20
`beats/min; then all individuals whose tachycardia is less than
`20/mii:i would be recorded as nonresponders, while all those
`with 20 or above .would be recorded as responders. . When the
`percent of re.sponcters in the population is plotted against the
`dose, a characteristic dose-response curve, more properly
`called a dose-cumulative frequency or dose-percent curve,
`is generated. Such a ·curve is, in fact, a cumulative .fre(cid:173)
`quency.:.distribution curve, the percent of responders at a
`given dose being the frequency of response. . ,
`Dose-cumwative frequency curves are generally of the same
`geometric shape as dose-intensity curves (namely, sigmoid)
`when frequency is -plotted against log dose (see Fig 37: $).
`The tendency of the cumulated frequency 'of response (ie,
`percent) to be linearly proportional to the log of the dose in
`the middle of the dose range is called the Weber-Fechner law,
`although it is not invariable', as a true natural law should be.
`In ~any instances, the cumulative frequency is simply pro(cid:173)
`f <>lt1on~ to dose rather than log dose. The Weber- Fechner
`
`aw applies to either dose- intensity or dose-cumulative fre(cid:173)
`dU.en~y data. The similarity between dose-frequency and
`. ose-1~tensity curves may be more than fortuitous, since. the
`inten.s1ty o~ response will usually have an approximately linear
`relat1onsh1p to· the percent of responding units (smooth
`m~cl~ cells, nerve fibers, etc) and hence is also a type of cu(cid:173)
`
`:a ~t1_ve frequency ofrespo~se. These are the same kind of
`
`·
`.t1at1cs that govern the law of mass action.
`n If only ~he increase in the number of responders with each
`8 ew ~ose is plotted, instead of the cumulative percent of re(cid:173)
`Pon ers, a bell-spaped curve is obtained. This curve is the
`
`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 freq1.1ency
`curve is symmetrically hyperbolic. Because most dose(cid:173)
`cumulative fre~uency curves are more nearly symmetrical
`when plotted semilogarithmically (ie, as. log dose), dose(cid:173)
`·
`cumulative frequency curves are usually log-normal.
`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-cum1.1lative
`frequency data, the ED50 (m.edian effective dose) is the dose
`to which 50% of the population responds (see Fig 37-5). If
`the frequency distribution is pormal, the ED50 is both the
`arithmetic mean and median dose and is represente<;I by the
`mid-point on the curve; if the distribution is log-normal, the .
`ED50 is the median'dose 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(cid:173)
`act.eristic of both the drug and test population. Even two
`drugs of identical mechanism may give rise to different slopes
`in dose-percent curves, when:1:1s in dose-intensity curves the
`slopes are the same.
`Statistical parameters (such as standard deviation)......:in
`addition t.o ED50, maximum cwnulative frequency (efficacy),
`the slope-characterize dose-cumulative frequency rela(cid:173)
`tionships (see Chapter 10).
`There are several formulations for dose-cumulative fre(cid:173)
`quency curves, some of which are employed only to define the
`li11e.ar segment of a curve and to .determint) the statistical
`parameters of this segment. For the statistical treatment of
`dose- frequency data, see Chapter 10. One,simple mathe(cid:173)
`matical expression of the entire log-symmetrical sigmoid curve
`is
`
`'
`)
`· { % response
`.log dose = K + f log oom
`1
`response
`10 -
`
`(1)
`
`where percent.'response may be either the percent of maxi(cid:173)
`mum intensity or the percent of a population responding.
`The.equation is thus basically the same for both log normal
`dose-intensity 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 t~e. pitfalls in~icated for dose-intensity co