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`InnoPharma Exhibit 1024.0001
`
`

`

`
`
`Acquisitions Editor: David B. Troy
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`Copyright 2000 Lippincott Williams 8c Wilkins
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`All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by
`any 111621115, inClUding photocopying, or utilized by any information storage and retrieval system Without written pel—
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`
`The publisher is not responsible (as a matter ot'product liability, negligence, or otherwise) for any 1nJury resulting;
`from any material contained herein. This publication contains information relating to general pl‘ll’lClplCS of me( —
`~
`. .
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`.
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`.
`.
`.
`-
`,
`i,
`., ..’
`'
`I
`.-
`Ical care that should not be construed as SchlIlC Instructions Ior 1nd1v1dual patients. ManuIaCttlchs product mlor
`mation and package inserts should be reviewed for current information, including contraindications, dosages. and
`precautions.
`
`Printed in the United States ofAmm‘ca
`
`Library of Congress Cataloging—in-Publication Data
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`Tozer, Thomas N.
`
`Introduction to pharmacokinetics and pharmacotlynamics : the quantitative basis ofdrug therapy / Thomas N-
`Tozer, Malcolm Rowland.
`p. ; cm.
`Includes index.
`ISBN 0-7817-5149—7
`
`1]. Tith-
`I. Rowland, Malcolm.
`1.Pharmacokinetics. 2. l)rugs—Physiological effect.
`[DNLM:
`I.
`l’harmaeokinetics. 2. Dose-Response Relationship, Drug. 3. Drug Therapy—melllOdS- 4-
`Pharmaceutical Preparations—administration 8c dosage. QV 38 T7571 2006]
`RM301.5.'I‘93 2006
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`The publishers have made wmy (flint to trace the copyight holders/or borrowed material. Ifthey have inadvertently overlooked any,
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`InnoPharma Exhibit 1024.0002
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`
`
`'
`
`pr
`‘ Maiammmmommn
`‘
`
`
`
`The reader will be able to:
`II Describe the characteristics of, and the differences between, first—order and zero—order
`absorption processes.
`I Estimate the bioavailability of a drug, given plasma concentration-time profiles following
`both extravascular and intravascular administration.
`I Define the following drug products: immediate—release, modified—release, extended—release,
`and delayed—release.
`II Estimate the relative bioavailability of a drug in different dosage forms given by the same
`route of administration or the same dosage form given by different routes of administration,
`when provided with appropriate plasma concentrationatime data,
`II Determine whether absorption or disposition rate limits drug elimination, given plasma
`concentration—time data following different dosage forms by the same route of
`administration or the same dosage form by different routes of administration.
`I: Anticipate the effect of altering the kinetics of absorption. extent of absorption, clear—
`ance, or volume of distribution on the systemic exposure—time following extravaswlar
`administration,
`
`I Describe the steps involved in the systemic absorption of a drug after oral
`administration.
`
`I: Distinguish between dissolution and permeability limitations in systemic absorption after
`oral administration.
`
`a Anticipate the role of gastric emptying and intestinal transit in the systemic absorption of
`a drug given orally with particular reference to the physicochernical properties of the d
`and its dosage form.
`“8
`Define bioequivalence and briefly describe how it is assessed.
`Anticipate the influence of food on the systemic absorption of a drug given orally
`
`
`InnoPharma Exhibit 1024.0003
`
`

`

`106
`
`SECTION II - Exposure and Response After a Single Dose
`
`D rugs are more frequently administered extravascularly (common routes are listed it]
`Table 6—1) than intravascularly, and the majority are mtended to
`syste1n1cally rather
`than locally. For these drugs, systemic absoI‘Ptlofla [he foals 9f thls Chapter: {5 a P“)-
`requisite for activity. Delays or losses of drug durmg Sysgem“? mpm-mf‘y comrlbme [‘0
`variability in drug response and occasionally may result in {allure of drug therapy- It ls
`primarily in this context, as a source OfV'driElblhly 1}] Syswmlc response and {15 a means
`of controlling the plasma concentration—time prollle, that systemic absorptlon IS CO“-
`sidered here and through the remainder of the bools. Keep 111 mind, 119WCVCI‘, that CV61}
`for those drugs that are used locally (e.g., mydriatics, local anesthetlcs, nasal deCOIl-
`gestants, topical agents, and aerosol bronchodllators), systemic absorptlon may 1111111-
`ence time ol'onset, intensity, and duration of adverse ellects.
`.
`This chapter deals primarily with the general prmctples governing “ate and extent
`of systemic drug absorption from the gastrointestinal tract. Although absorptlon iron1
`other ext “avascular sites is discussed, emphasis is placed on systemic absorptlon follow.
`ing oral administration. This is not only because the oral mode 'ol‘ administration is the
`most prevalent for systemically acting drugs, but also becauseit illustrates many sources
`of variability encountered with extravascular administratlon 1n general.
`A number of oral dosage forms are available. Some are liquids (syrups, elixirx,
`tinctures, suspensions, and emulsions), whereas the more common ones are solids
`(tablets and capsules). Tablets and capsules are generally lormulated to release drug
`immediately after their administration to hasten systemic absorption. Thes ‘ are called
`immediate-release products. Other products, modified—release dosage forms, have
`been developed to release drug at a controlled rate. The purpose here is generally
`either to avoid contact with gastric fluids (acidic environment) or to prolong drug input
`into the systemic circulation.
`Modified-release products fall into two categories. One is extended-release, a dosage
`form that allows a reduction in dosing frequency or diminishes the fluctuation of drug
`levels on repeated administration compared with that observed with immediate—release
`dosage forms. Controlled-release and sustained-release products fall into this category,
`The second category is that ot‘delayed—release. This kind of dosage form releases drug, in
`part or in total, at a time other than promptly afte * administration. Enteric—coated dosage
`forms are the most common delayed-release products; they are designed to prevent
`release of drug in the stomach, where the drug may decompose in the acidic environment
`or cause gastric irritation, and then to rel ‘ase drug for immediate absorption once in the
`intestine. Modified-release products are also administered by nonoral extravascular
`routes. For example, repository (depot) dosage forms are given intramuscularly and suly
`cutaneously in the form of emulsions, solutions in oil, suspensions, and tablet implants.
`
`
`
`:TABLEllGETI Extravascular Routes of Administration for Systemic Drug Deliverya
`
`Buccal
`
`Oral
`
`Via alimentary canal
`
`Other routes
`
`Rectal
`
`Sublingua]
`
`Subcutaneous
`Inhalation
`Transderma]
`Intramuscular
`Intranasal
`
`“Routes such as dermal, intra-articular, intrathecal, intravaginal, ocular, subdural, and so on,
`are usually used for local effect.
`
`InnoPharma Exhibit 1024.0004
`
`

`

`CHAPTER 6 l Extravascular Dose and Systemic Absorption
`
`107
`
`
`
`The oral absorption of drugs often approximates first-order kinetics, especially when
`given in solution. The same holds true for the systemic absorption of drugs from many
`other extravascular sites, including subcutaneous tissue and muscle. Under these cir—
`cumstances, absorption is characterized by an absorption rate constant, Ira. The corre-
`sponding absorption half-life, [WW is related to the absorption rate constant in the same
`way that elimination half—life is related to elin’iination rate constant, that is,
`
`0.693
`[m
`
`ILq. 6-]
`
`ll/2,u :
`
`The half-lives for the absorption of drugs administered orally in solution or in a rapidly
`dissolving (immediate-release) dosage form usually range from 20 minutes to 3 hours‘
`Occasionally, they are longer, especially if dissolution or release from the dosage form
`is slow.
`
`When absorption occurs by a first—order process,
`
`Rate 0 V
`
`Absorpium
`
`=
`
`Ira
`.
`Absorption
`rate constant
`
`-
`
`Au
`Amount
`remaining
`to be absorbed
`
`,
`Eq. 6-2
`
`The rate is proportional to the amount remaining to be absorbed, Aa. First-order absorp-
`tion is scl‘iematically depicted in Fig. 6—1 by the emptying of water from a cylindrical
`bucket. The rate of emptying depends on the amount of water in the bucket and the
`size of the hole at the bottom. With time, the level ofwater decreases, reducing the rate
`at which water leaves the bucket. Indeed, the rate ofemptying is directly proportional
`to the level or amount ofwater in the bucket.
`Sometimes, a drug is absorbed at essentially a constant rate. The absorption kinet—
`ics is then called zero order. Differences between first-order and zero-order kinetics are
`illustrated in Fig. 6—2. For zero-order absorption, a plot of amount remaining to be ab—
`sorbed against time yields a straight line, the slope of which is the rate of absorption
`
`Rateofemptying
`
`ka
`
`Time
`
`
`First-order systemic absorption is analogous to the emptying of water from a hole in the b0
`FIGURE“ _ ]
`ttom of a cylin-
`0 also decreases
`drical bucket. The level of water in the bucket decreases with time, as does the rate at which it does 5
`with time.The slowing of the decline of the water level and the rate of emptying are due to the decrease in water
`res-
`sure, which depends on the water level (or amount of water) in the bucket.The rate of emptying (g/min) which decpunes
`exponentially with time, is proportional to the amount (g) of water in the bucket and the size of the hole. The rate of
`emptying relative to the amount in the bucket is the fractional rate of emptying, which does not vary with time In
`absorption terms, this constant is called the absorption rate constant, ka.
`
`InnoPharma Exhibit 1024.0005
`
`

`

`108
`
`SECTION it I Exposure and Response After a Single Dose
`
`A
`
`100
`
`at)
`
`9’2»;
`
`N
`
`50
`
`{Ed
`w 40
`5:? 0
`mm
`a"
`
`20
`
`0-
`
`0
`
`6
`
`12
`Hours
`
`18
`
`24
`
`B
`
`100
`
`Eu
`EB
`gs
`mg
`E:
`mm
`2 o
`an-
`n-
`
`10
`
`1
`
`o
`
`6
`
`12
`HOUI‘S
`
`18
`
`24
`
` ‘
`A comparison of zero—order (colored lines) and first-order (black lines) absorption processes Depicted are reg
`ular (A) and semitogarithmic (B) plots of the percent remaining to be absorbed against time. Note the curvatures of the
`two processes on the two plots.
`
`(mi; (342A). Recall from Chapter 5 that the fractional rate of decline is constant for a
`first—order process; the amount declines linearly with time when plotted semilogari1h~
`mically. in contrast, for a Zero—order absorption process, the fractional rate increases
`with time, because the rate is constant whereas the amount remaining to be absorbed
`decreases. This is reflected in an ever—h1creasingly negative gradient with time in a semi—
`logaritlnnic plot of the amount remaining to be absorbed (Fig. ii—2B).
`For the, remainder of this chapter, and for much oi" the book, systemic absorption
`is modeled as a Iirst~order process. When it is zero order, the equations subsequently
`developed in (lhapter 9 apply.
`
`EXPOSURE-TIME AND EXPOSURE—DOSE RELATIONSHIPS
`
`The systemic exposure to a drug after a single extravascular dose depends on both sys-
`temic absorption and disposition. (Ionsider first how exposure with time alter an extra—
`vascular (lose compares with that seen alter an intravenous dose.
`
`Extravascular versus Intravenous Administration
`
`Absorption delays and reduces the triagnitude ol'peak plasma concentration compared
`with that seen alter an equal intravenous bolus dose. 'l'hese eil'ects are portrayed for
`aspirin in Fig. (3—3.
`The iise and tall ol'the drug concentration in plasma alter extravascnlar adminis—
`tration are best understood by realizing that at any time,
`
`Rule of
`change of =
`drug" in Daily
`
`Krt ‘ do,
`Rate of
`absorption
`
`—
`
`Ir - rl
`Rate of
`elimination
`
`liq. (3 —3
`
`InnoPharma Exhibit 1024.0006
`
`

`

`CHAPTER 6 I Extravascular Dose and Systemic Absorption
`
`109
`
`10
`
`8
`
`6
`
`j
`?!)
`g 4
`
`2
`
`0
`
`
`
`PlasmaAspirinConcentration
`
`Aspirin (650 mg) was ad—
`ministered as an intravenous bolus (black) and
`as an oral solution (color) on separate occa—
`sions to the same individual.Absorption causes
`a delay and a lowering of the peak concentra-
`tion (1 mg/L = 5.5 uM). (Modifiedfrom the
`data of Rowland M, Riegelman 5, Harris PA,
`et al. Absorption kinetics ofaspirin in man fol-
`lowing oral administration ofan aqueous solu-
`tion. 1 Pharm Sci 1972;67:379—385. Adapted
`with permission of the copyright owner.)
`
`0
`
`20
`
`40
`
`60
`Minutes
`
`80
`
`100
`
`120
`
`The scheme in Fig. 6—4 illustrates the expectation. Drug is input into the reservoir
`by a first—order process and is eliminated in the same manner as that following an intra-
`venous (lose (see Fig. 5—3).
`Initially, with the entire (lose at the absorption site (bucket) and none in the body
`(reservoir), rate ol‘ absorption is maximal and rate ofelinlination is zero. Therefore, as
`drug is absorbed, its rate ol'absorption decreases, whereas as concentration in the reser—
`voir rises, its rate ol’elimination increases. Consequently, the difference between the two
`rates diminishes. As long as the rate of absorption exceeds that of elimination the con-
`centration in the reservoir continues to rise. Eventually, a time, tum, is reached when the
`rate of'elinlination matches the rate of absorption; the concentration is then at a maxi—
`mum, Cnm. Subsequently, the rate. ol‘elimination exceeds the rate of absorption and the
`concentration declines, as shown in Fig.
`for the plasma concentration ofaspirin after
`a single oral (lose.
`
`
`
`
`
`InputRate
`
`Time
`
`Reservoir
`
`
`
`Exuactor
`
`‘
`
`Fraction extracted during
`passage through extractor, E
`
`Scheme forthe first-order
`FIGURE 6—4
`systemic absorption and elimination of a drug
`after a single extravascular dose.The systemic
`absorption is simulated by the emptying of a
`water bucket (see Fig. 6—1).The rate constant
`for absorption ka is the fractional rate of ab-
`sorption, that is, the rate of absorption relative
`to the amount in the bucket. The elimination
`of the drug from the body (see Fig. 5~3) de-
`pends on the extent of its tissue distribution
`lvolume of reservoir, V), and how well the drug
`IS extracted from the fluid going to the elimi-
`nating organ (5) (as measured by CL). In this
`integrated model, the amount of water added
`to the reservoir is negligible, as is the amount
`of drug in the extractor and in the fluid going
`to the extractor, relative to the amount in the
`,esewoir.
`
`InnoPharma Exhibit 1024.0007
`
`

`

`1 10
`
`SECTION II I Exposure and Response After a Single Dose
`
`The p *ak plasma concentration following extravascular administration is lower
`than the initial value following an equal intravenous bolus dose. In the former case, at
`the peak time some drug remains at the absorption site and some has already been elimt
`inated, while the entire (lose is in the body immediately following the intravenous dose,
`Beyond the peak time, the plasma concentration exceeds that following intravenous
`administration of the same dose when absorption is complete (total areas are the same)
`because of continued entry of drug into the body,
`Frequently, the rising portion of the plasma concentration-time curve is called the
`absorption phase and the declining portion, the elimination phase. As will subsequently
`be seen, this description may be misleading. Also, if the entire dose does not reach the
`systemic circulation, the drug concentration may remain lower than that observed after
`intravenous administration at all times.
`
`Absorption influences the time course of drug in the body; but what of the total
`area under the exposure-time profile, A UC ? Recall from Chapter 5 that the rate ofelinL
`ination is:
`
`Rate ofelimination = (IL-(J
`
`Eq. 6-4
`
`Integrating over all time,
`
`Total amount eliminated 2 CL- AUC
`
`Eq. 6-5
`
`The total amount eliminated after an oral dose equals the total amount absorbed,
`1" Dose, where the parameter 1'; bioavailability, takes into account that only this frao
`tion of the oral dose reaches the systemic circulation. That is,
`
`F - Dose
`Total amount
`absorbed
`
`=
`
`CI. ' A UC
`Total amount
`eliminated
`
`Eq. 6—6
`
`Bioavailability
`
`Systemic absorption is often incomplete when given extravascularly, for reasons to be
`discussed subsequently. Knowing the extent of absorption (bioavailability) helps to en~
`sure that the correct dose is given extravascularly to achieve a therapeutic systemic expo~
`sure. Although dose is known and area can be determined following an extravascular
`dose, from Eq. 6—6 it is apparent that clearance is needed to estimate bioavailability.
`Recall, from Chapter 5 (Eq. 5-21), that to determine clearance, a drug must be given
`intravascularly, as only then is the amount entering the systemic circulation known (the
`dose, F = 1). Therefore,
`
`Dose,“ = Clearance-AUG,“
`
`Eq. 6-7
`
`After an extravascular (ev) (lose,
`
`['27, ~1)0.s‘(am = Cleara'naz- A UC,.,,
`
`Eq. 6—8
`
`Which, upon division of Equation 6-8 by Equation 6-7 and given that clearance is un—
`changed, yields
`
`I'I’“ : { AU6”,
`
`AUG”,
`
`
`
`( Bosch, )
`
`I)ose,,,,
`
`Eq' (39
`
`InnoPharma Exhibit 1024.0008
`
`

`

`CHAPTER 6 II Extravascular Dose and Systemic Absorption
`
`1 11
`
`For example, if the area ratio for the SZIII’IC dose administered orally and ii'itravenously is
`0.5, only 50% of the oral dose must have been absorbed systematically.
`
`Relative Bioavailability
`
`Relative bioavailability is determined when there are no intravenous data. Cost to develop,
`instability, poor solubility, potential adverse events, and lack of regulatory approval
`are major reasons for the lack of an intravenous preparation. Relative bioavailability is
`determined by comparing the fractions absorbed for different dosage forms, different
`routes ofadmii'iistration, or different conditions (e.g., diet or presence of another drug).
`Thus, taking the general case of two dosage forms:
`
`Dosage Form A
`
`Dosage Form B
`
`So that,
`
`FA ' Dose,‘
`Total amount
`absorbed
`
`= Clearance ‘ AUCA
`Total amount
`eliminated
`
`F], - 0056,,
`Total amount
`absorbed
`
`= Clearance ' A UCB
`Total amount
`eliminated
`
`Eq. 6-10
`
`Eq. 6-11
`
`E( . 6-12
`I
`
`
`AUC‘
`Dose
`Relative liioavailabzlili = (
`’
`If
`3
`g A UC,,
`Dose/1
`
`.
`
`,
`
`_
`
`This relationship holds, regardless of the extravascular route of administration, rate of
`absorption, or shape of the curve. Constancy of clearance is the only requirement.
`
`
`
`The concentration—time profile following a change in dose or in the absorption char—
`acteristics of a dosage form can be anticipated.
`
`Changing Dose
`
`If all other factors remain constant, as anticipated intuitively, increasing the dose or
`the fraction of a dose absorbed produces a proportional increase in plasma concentra-
`‘
`'
`»
`v
`r
`x
`‘
`,
`.
`tion at all times. The value of tmux iemains unchanged, but (rum and AUC increase pro—
`portionally with dose.
`
`Changing Absorption Kinetics
`
`Alterations in absorption kinetics, for example, by changing dosage form or giving the
`product with food, produce changes in the time profiles of the plasma concentration.
`This point is illustrated by the three Situations depicted in the seinilogarithmic plots of
`Fig. (3-5 involving only a change in the absorption half-life. All other factors (extent of
`
`InnoPharma Exhibit 1024.0009
`
`

`

`1000
`
`100
`
`10
`
`
`
`Rate(mg/hr)
`
`Case A
`
`1
`
`0
`
`5
`
`12
`
`18
`
`24
`
`Hours
`
`1000
`
`100
`
`10
`
`
`
`Rate(mg/hr)
`
`Case B
`
`1
`
`1000
`
`100
`
`10
`
`
`
`Rate(mg/hr)
`
`6
`
`12
`
`18
`
`24
`
`Hours
`
`10
`
`
`
`PlasmaDrugConcentration(mg/L) 0
`
`o_o1
`
`0
`
`10
`
`—L
`
`
`
`PlasmaDrugConcentration(mg/L) P
`
`0 01
`
`0
`
`10
`
`
`
`PlasmaDrugConcentration(mg/L) 0
`
`6
`
`12
`
`18
`
`24
`
`Hours
`
`6
`
`12
`
`18
`
`24
`
`Hours
`
`Case C
`
`1
`
`0
`
`6
`
`12
`Hours
`
`18
`
`24
`
`0 01
`
`0
`
`6
`
`12
`Hours
`
`18
`
`24
`
`Rates of absorption (colored line) and elimination (black line) with time (graphs on left) and corresponding
`plasma concentration-time profiles (graphs on right) following a single oral dose of drug under different input conditions.A
`slowing (from top to bottom) of drug absorption delays the attainment (tm) and decreases the magnitude (Cm) of the peak
`plasma drug concentration. In Cases A and B (top two sets ofgraphs), the absorption process is faster than that of elimination
`and elimination rate limits the decline of the concentration. In Case C (bottom setofgraphs), absorption rate limits elimina—
`tion 50 that the decline of drug in plasma reflects absorption rather than elimination. Because there is a net elimination of
`drug during the decline phase, the rate of elimination is slightly greater than the rate of absorption. in all three cases, bioavail—
`ability is 1.0 and clearance is unchanged. Consequently, the areas under the plasma concentration—time curves (correspond—
`ing linear plots of the top three graphs) are identical.The AUCs of the linear plots of the rate data are also equal because the
`integral of the rate of absorption, amount absorbed, equals the integral of the rate of elimination, amount eliminated.
`
`InnoPharma Exhibit 1024.0010
`
`

`

`CHAPTER 6 I Extravascular Dose and Systemic Absorption
`
`113
`
`absorption, cl ‘arance, and volume ofdistribution and hence elimination halt—lite) re—
`main unchanged.
`
`Disposition is Rate Limiting
`
`In Case A, the most common situation, absorption half-life is much shorter than
`elimination half—life. In this case, most of the drug has been absorbed and little has been
`eliminated by the time the peak is reached. Thereafter, decline of drug is determined
`primarily by the disposition oi'the drug, that is, disposition is the rate—limiting step. The
`half—life estimated from the decline phase is therefore the eliinil- ttion half—life.
`In Case B, absorption half—life is longer than in Case A but, still shorter than elimi—
`nation halillil‘e. The peak occurs later (tum increased) because it takes longer for the
`concentration to reach the value at which rate of elimination matches rate ofabsorp--
`tion; the. Cum, is lower because less drug has been absorbed by that time. liven so, absorp—
`tion is still essentially complete before the majority of drug has been elin’iinatcd.
`Consequently, disposition remains the rate-limitingr step, and the terminal decline still
`reflects the Clilnil‘laiiOll half—life.
`
`Absorption is Rate Limiting
`
`Occasionally, al*)sor}‘)tion half—life is longer than elimination hallllife, and Case C prevails
`(Fig. (3—5) . The peak concentration occurs later yet and is lower than in the two previous
`cases, reflecting the slower absorption process. Again, during the rise to the peak, the
`rate of elimination increases and eventual] 7, at the p ‘ak equals the rate of absorption.
`However, in contrast to the previous situations, absorption is now so slow that consider—
`able drug remains to be absorbed well beyond the peak time. Furthermore, at all times
`most of the drug is either at the absorption site or has been eliminated; little is ever in
`the body. In fact, during the decline phase, drug is eliminated virtually as fast as it is
`absorbed. Absorption is now the “ate—limiting step. Under these circumstances, since
`the rate ofelimination essentially matches the rate ol'absorption, the following approx—
`imation (2) can be written:
`
`That is,
`
`N
`
`k - A
`Rate of
`
`lea ' An
`Rate of
`
`elimination
`
`absorption
`
`A
`
`z
`
`Amount
`
`in body
`
`[m
`—— via
`k
`Amount
`
`remaining to
`be absorbed
`
`I‘Iq. (3-13
`
`1.;(1' (3.14
`
`Accordingly, the plasma concentration (C: A/V) during the decline Phase is
`directly proportional to the amount remaining to be absorbed. For example, when an,
`amount remaining to be absorbed falls by one-half so does the plasma C()ncelm,mi0n.
`of
`The time required for this to occur is the absorption hallllii‘e. That is, the half—life
`decline of drug in the body now corresponds to the absorption halillifc. Flip
`-flop is a
`common descriptor for this kinetic situation. When it occurs, the ter
`ms absorption
`
`InnoPharma Exhibit 1024.0011
`
`

`

`1 14
`
`SECTION II I Exposure and Response After a Single Dose
`
`phase and elimination phase for the regions where the plasma concentration—time curve
`rises and falls, respectively, are cl ’arly misleading.
`
`Distinguishing Between Absorption and Disposition Rate Limitations
`Although disposition gene ‘ally is rate-limiting, the preceding discusston suggests that can—
`the meaning ofhall—hle deternuned from the
`tion should be exercised in interpreting
`I
`I
`.
`I
`_
`tration. Confuston 1s avoided if the drug is
`decline phase following extravascular adminis
`‘
`‘
`also given intravenously. In practice, however, intravenous dosage Iorms 01 many drugs
`do not exist for clinical use. Absorption and disposition rate hmltauons may be distm—
`guished by altering the absorption kinetics of the drug. This is most readily accomplished
`by giving the drug either in another dosage form such as a solution or by a different route.
`
`
`
`Systemic absorption is favored after extravascular administration because the body acts
`as a sink, producing a concent‘ation difference between the diffusible unbound con-
`centrations at the absorption site and in systemic blood. The concentration gradient
`across the gastrointestinal absorptive membranes is maintained by distribution to tis—
`sues and elimination of absorbed drug. Physiologic and physical factors that determine
`movement of drug through membranes in general are discussed in Chapter 4. In eluded
`among them were the physicochemical properties of the drug, the nature of the mem—
`brane, presence of transporters, perfusion, and pH. These factors and others are now
`considered with respect to drug passage through the gastrointestinal membranes. In
`this context, absorption is the term that is subsequently used for this process.
`However, before a drug can pass through the membranes dividing th ) absorption
`site from the blood, it must be in solution. Most drugs are administered as solid prepa-
`rations. Common examplcs are tablets and capsules. Before addressing the issues involv—
`ing drug release from a solid dosage form, let us first consider the events that result in
`systemic absorption after oral zulministration of a drug in solution.
`
`Gastrointestinal Absorption
`
`In accordance with the prediction of the pH partition hypothesis, weak acids are ab—
`sorbed more rapidly from the stomach at pH 1.0 than at pH 8.0, and the converse holds
`for weak bases. Absorption of acids, however, is much faster from the less acidic small
`intestine (pH 6.6 to 7.5) than from the stomach. These apparently conflicting observa—
`tions can be reconciled. Surface area, permeability and, when perfusion rate limits
`absorption, blood flow are important determinants of the rapidity of absorption. The
`intestine, especially the small intestine, is favored on all accounts. The total absorptive
`area of the small intestine, produced largely by microvilli, has been calculated to be about
`200 Mi), and an estimated 1 L of blood passes through the intestinal capillaries each
`minute. The corresponding estimates for the stomach are only I M2 and 150 nth/min.
`The perm "ability of the intestinal membranes to drugs is also greater than that of the
`stomach. These increases in surface area, permeability, and blood flow more than com-
`pensate for the decreased fraction ofun-ionized acid in the intestine. Indeed, the absorp—
`tion of allcompounds—acids, bases, and neutral compounds—is faster from the (small)
`intestine than from the stomach. Because absorption is gr *ater in the small intestine, the
`rate of gastric emptying is a controlling step in the speed of drug absorption.
`
`InnoPharma Exhibit 1024.0012
`
`

`

`CHAPTER 6 I Extravascular Dose and Systemic Absorption
`
`115
`
`Gastric Emptying
`
`Food, especially fat, slows gastric emptying, which explains why drugs are frequently rec-
`ommended to be taken on an empty stomach when a rapid onset of action is desired.
`Drugs that influence gastric emptying also affect the rate of absorption ofother drugs,
`as shown in Fig. 6—6 for acetaminophen, a common analgesic/antipyretic.
`Retention of acetaminophen in the stomach increases the percentage of a dose
`absorbed through the gastric mucosa, but the majority of the dose is still absorbed
`through the intestinal epithelium. In this regard, the stomach may be Viewed as a repos—
`itory organ from which pulses of drug are ejected by peristalsis onto the absorption sites
`in the small intestine.
`
`Intestinal Absorption
`
`Throughout its length, the intestine varies in its multifaceted properties and luminal
`composition. The intestine may be broadly divided into the small and large intestines
`separated by the ileocecal valve. Surface area per unit length decreases from the duo-
`denum to the rectum. Electrical resistance, a measure of the degree of tightness of the
`junctions between the epithelial cells, is much higher in the colon than in the small
`intestine. Proteolytic and metabolic enzymes, as well as active and facilitated transport
`systems, are distributed variably along the intestine, often in restrictive regions. The
`colon abounds with anaerobic microllora. The mean pH, 6.6, in the proximal small
`intestine rises to 7.5 in the terminal ileum, and then falls sharply to 6.4 at the start of the
`cecum before finally rising again to 7.0 in the descending colon. Transit time of ma-
`terials is around 3 to 4 hours in the small intestine and from 10 to 36 hours or even
`longer in the large bowel. Although these and other complexities make precise quanti—
`tative prediction ofintestinal drug absorption difficult, several general features emerge.
`The permeability-surface area product (1’ ' SA) tends to decrease progressively from
`duodenum to colon. This applies to all drug molecules traversing the intestine epithe-
`liuIn by non—carrier—mediated processes, whether via the transcellular (tl’1rough cell) or
`paracellular (around cells) routes, when drugs are placed in different parts ofthe intes-
`tine, as illustrated in Fig. 6—7 for ranitidine. The extent ofabsorption is decreased when
`ranitidine is administered into the eecum as reflected by the reduced AUC (Fig. 6—7A).
`
`
`
`PlasmaAcetaminophen
`
`(mg/L)
`Concentration
`
`m Slowing gastric emptying
`by propantheline (30 mg intravenous) slows the
`rate ofabsorption of acetaminophen (1 SOO-mg
`dose) ingested orally by a 22-year-old man, as
`seen by a decrease in the maximum plasma
`concentration and a longer time to reach this
`concentration (-----~) compared with values when
`
`acetaminophen is given alone (
`Meto-
`clopramide (10 mg intravenous), which short-
`ens the time for gastric emptying, hastens the
`absorption of acetaminophen (- - -). (Redrawn
`from Nimmo 1, Heading RC, Tothill P, et al.
`Pharmacological modification ofgastric emp-
`tying: effects of propantheline and metoclo-
`pramlde on paracetamol (acetaminophen)
`absorption. Br Med] 7973; 7:587—588.)
`
`InnoPharma Exhibit 1024.0013
`
`

`

`1 16
`
`SECTION II I Exposure and Response After a Single Dose
`
`t, W
`‘2.
`
`A
`
`/\ 500 -
`~—-l
`g E, 400
`3-3- v
`'5 g 300
`m “e
`g? 200
`m ‘5
`(u 0
`a S 100
`Q
`
`0
`
`
`
`B
`
`m: 1000
`E 5
`gé
`5.5
`n: a
`to b
`c
`5 8
`E I:
`n. o
`
`Hours
`
`Q
`
`10 ONWWTM‘PME‘Wfiz
`Hours
`
`'ihe gastrointestinal absorption of ranititline varies with site of applicationihe variation is shown in linear
`FIGURE, 6-7
`(A) and Sfitllil'rgarithnrie (B) plots of the rrrean plasr'na UNILQIIllalitflhtifl'le profiles of ranilrriine observori after placing
`an aqueous solution (6 ml.) containing 'iSOmgofraniticline hydrochloride irrtotire stomach (.),jejununr (A), and colon
`(ll) of eight volur‘rteers via a nasoenrer ic tube. 1 he much less extensive absorption of this small (MW : 3'13 g/mol) polar
`r‘nolerlrle from the Lolon is consistent with the idea that the pernreabilitysurface area (P - SA) plOleLt is much lower
`in the colon than in the small intestine. Notice that absorption of ranitidine effettively ceases (in terminal decline
`phase) by 3 hours when placed in the stomach orjejrrrrunr, even though the drug is incompletely bioavailable ( :
`0.6; data not shown). 1 his suggests that the small intestine is the major site of absorption when ranitidine is taken
`orally. Also, notite