`

`
`
`A (:qu.z'sitiom' Editor." David B. Troy
`Mmmgingli/lilov‘: Andrea Klingler
`Mar/ret1'ngMrnmgvr: Marisa O’Brien
`Prozluction Edz'lor: Jennifer I’. Ajello
`I)esigm:r.' Doug Smock
`Com/msz'l0r.' Circle Graphics
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`ical care that should not be construed as spccilic instructions for individual patients. Manufacturers’ product mlor-
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`precautions.
`
`I’rin/Ml in the United States ofzl7Izcnm
`
`Library of Congress Cataloging-in-Publication Data
`
`Tozer, Thomas N.
`
`Introduction to pharmacokinetics and pharmacodynamics : the quantitative basis ofdrug therapy / Thom?“ N-
`Tozer, Malcolm Rowland.
`p. ; cm.
`Includes index.
`ISBN 0-7817-5149-7
`
`I]. Title.
`I. Rowland, Malcolm.
`1.Pharmacokineties. 2. 1)rugs——l’hysiological effect.
`[DNLM:
`I. Pharmaeokineties. 2. Dose-Response Relationship, Drug. 3. Drug ThC“‘PY“‘n€lhOdS'
`Pharmaceutical l’reparati<ms—administration & dosage. QV 38 T757i 2006]
`1{M30l.5.'T93 2006
`
`4‘
`
`Gl5'.7—(lc22
`
`2005044550
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`'I‘1m/1ublis/my have mrule every zyjbrt lo h'ltL‘t.’ the copyvig/it l1.oI(lL>rxfor b()W‘()1Ut.’(l material. Ifthey have ina(lvcrIm!ly overlooked any,
`they will be ]}]B(lS(,'(l to maize the rzrzcexmry awangm/zents at t/11:/Zrst 0])/Iortunity.
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`To purchase additional copies ofthis book, call our customer service department at (800) 638-3030 or fax OI'(l€1'S I0
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`06 ()7 080910
`12345678910
`
`|nnoPharma Exhibit 1024.0002
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`,, W."---v-vv-W-h,.
`
`...M..,.......,.~.hv..,..J,.
`
`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: imrnediate—release, rnodified—release, extended—release,
`and delayed—release.
`I 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 concentration«tirne data.
`I Determine whether absorption or disposition rate limits drug elimination, given plasma
`concentration—tirne data following different dosage forms by the same route of
`administration or the same dosage form by different routes of administration.
`In Anticipate the effect of altering the kinetics of absorption. extent of absorption, clear-
`ance, or volume of distribution on the systemic e><posure—tirne following extravascuiar
`administration.
`
`I: Describe the steps involved in the systemic absorption of a drug after oral
`administration.
`
`:1 Distinguish between dissolution and permeability limitations in systemic absorption after
`oral administration.
`
`:1 Anticipate the role of gastric emptying and intestinal transit in the systemic absorption of
`a drug iven orally with particular reference to the physicoch '
`'
`1
`-
`_
`and itslfilosage form.
`emlca pmpemes of the drug
`Define bioequivalence and briefly describe how it is assessed.
`Anticipate the influence of food on the systemic absorption of a drug given orally
`
`
`|nnoPharma Exhibit 1024.0003
`
`

`

`106
`
`SECTION II - Exposure and Response After a Single D059
`
`listed ll}
`D rugs are more frequently administered extravascularl)’ (Common 1‘0UlCS '<.11”€
`Table 6-1) than intravascularly, and the majority are intended to
`systemically rathflr
`than locally. For these drugs, systemic absoI‘P“0l1= the foals ff thls Chapter: ls 3 P“?-
`requisite for activity. Delays or losses of drug durmg Syslenll? mput may Conmbute {P
`variability in drug response and occasionally may result in {allure of drug ll1€1‘apy-
`It ls
`primarily in this context, as a source Of‘V’r\Fl€1b1hlY 1}‘ Syslcmlc resfionse mld €15 3 _means
`of controlling the plasma concentration-time prohle, that ‘systemic absorptlotl 1S C0’)-
`sidered here and through the remainder of the boOls- KC€P 111 mmd, l1(.)W€VC1‘,
`that CV61}
`for those drugs that are used locally (e.g., mydriatics, local zmestlietics, nasal deem}-
`gestants, topical agents, '.1nd aerosol bronchodilators), ‘systemic absorption may 1nfl11_
`ence time ofonset, intensity, and duration of adverse ellects.
`.
`This chapter deals primarily with the general principles governing rate and extent
`ofsysteinic drtig absorption from the gastrointestinal tract. Although absorption iroih
`other extravascular sites is discussed, emphasis is placed on systemic absorption follow.
`mg oral admiiiistration. This is not only because the oral mode ‘of administration is the
`most prevalent for systemically acting drugs, but also l')€C21.L1SC.lt illustrates many sources
`of variability encountered with extravascular administration in general.
`A number of oral dosage forms are available. Some are liquids (syrups, elixirx,
`tinctures, suspensions, and emulsions), whereas the more Common Ones are S0liCls
`(tablets and capsules). Tablets and capsules are generally forrnt1late(l to release drug
`immediately after their administration to hasten systemic absorption. These 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 a(lministration compared with that observed with immediate-release
`dosage forms. Controlled-release and sustained-release products fall into this category,
`The second category is that ofdelayed—release. This kind of dosage form releases drug, in
`part or in total, at a time other than promptly after 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 release drug for immediate absorption once in the
`intestine. Modified-release products are also administered by iionoral extravascular
`routes. For example, repository (depot) dosage forms are given intramuscularly and sub—
`cutaneously in the form of emulsions, soltitioiis in oil, suspensions, and tablet implants.
`
`
`
`:'l'ABLEll65_‘l Extravascular Routes of Administration for Systemic Drug Delivery?‘
`
`Bucca]
`
`Oral
`
`Via alimentary canal
`
`Other routes
`
`Rectal
`
`Siiblingual
`
`Subcutaneous
`Inhalation
`Transdermal
`In traniuscular
`Iiitraiiasal
`
`"Routes such as (leriiial, iiitra—articular, intratliecal, intravaginal, ocular, subdural, and so on,
`are usually used for local effect.
`
`|nnoPharma Exhibit 1024.0004
`
`

`

`CHAPTER 6 I Extravascular Dose and Systemic Absorption
`
`107
`
`
`
`Tl1e oral absorption of drugs often approximates I'irst-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 characteri7.ed by an absorption rate constant, ka. The corre-
`sponding absorption l1all'-life, l,/._,‘“, is related to the absorption rate constant in the same
`way that elimination hall1lil'e is related to elimination rate constant, that is,
`
`0.693
`
`lm.
`
`ti/2,”
`
`Eq. 6-]
`
`Tl1e hall’-lives for the absorption of drugs administered orally in solution or in a rapidly
`dissolving (immediate-release) dosage form usually range fronl 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,
`
`Pizza 0 l
`i
`Absor/2/1.()n.
`
`=
`
`/ca
`_
`Absorption
`rate constant
`
`-
`
`Au,
`Amount
`remaining
`t.o be absorbed
`
`.
`Eq. 6-2
`
`The rate is proportional to the amount remaining to be absorbed, Aa. First-order absorp-
`tion is schematically depicted i11 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 oliemptying is (lirectly proportional
`to the level or amount ofwater iii the bucket.
`Sometimes, a drug is absorbed at essentially a constant rate. The absorption kinet-
`ics is then called zero order. I)ill‘erences between lirst-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 wl1icl1 is the rate of absorption
`
`Rateofemptying
`
`ka
`
`Time
`
`
`First-order systemic absorption is analogous to the emptying of water from a hole in the go
`‘FIGUREH _ ]
`ttom ofa cylin-
`drical bucket. The level of water in the bucket decreases with time, as does the rate at which it does so ago decreases
`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 defines
`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.
`
`|nnoPharma Exhibit 1024.0005
`
`

`

`108
`
`SECTION II I Exposure and Response After a Single Dose
`
`A
`
`100
`
`1‘-"’~cs
`
`N ‘5
`Egg
`“fez
`E: W
`93”’
`>-- 0
`;‘§_”""
`
`80
`
`60
`
`(10
`"
`
`2D
`
`0.
`
`0
`
`B
`
`100
`
`E1:
`:3
`E 3
`tug
`m<
`E 41
`0.11:!
`2 o(DI-
`9-
`
`10
`
`1
`
`0
`
`6
`
`12
`Hours
`
`18
`
`24
`
`6
`
`12
`HOUTS
`
`18
`
`24
`
` y
`A comparison of zero—order (colored lines) and first—order(blackli11es) absorption processes. Depicted are reg~
`utatr (A) and semilogarithmic (B) plots of the percent remaining to be absorbed against time. Note the curvatures of the
`‘two processes on the two plots.
`
`l{c*('all i‘1'o11‘1 (".l1'.1ptc:1' 5 that the t'1'21(:ti<>1‘121l rate <>I’(1e('|i11té is <'<)1‘1st2111t for 21
`(1"i.%'~ (3~2A).
`[i1*st—o1‘(ic1'pmttess; the 21111011111 (lt~cli1'1es lint-211‘ly with time when plotted st—*111ilr>ga1‘itl1~
`ttiically. I11 tzontrast, for a zcm—o1‘(lc1‘ al)s0rpti<)11 pmccss, the h".1('ti()11al rate i11(‘.l"(f}|sCS
`witI1 time, |)cca11sc ll)I;‘1"dtC is ('o11sta11t. witt-1'cas tho 21111011111 11-11121i11i11g to he al)so1‘|)et|
`(l<:(‘1‘cascs. This is l‘t3fl(,‘ClC(i in an evt-r1'—i1tcrcasingly iicgativc g1'21(lic11t with time in 21st-mi-
`io;;';11'itl1111i(‘.plntotitltc:a111n1111t1‘e1nz1i11i11gt()he;1|)s(>1‘l)c(l (Fig. t')—2B).
`For the 1‘c11121i11(tc1' of tI1is chaptet‘, and Ik)1‘11111(:I1 01' the hook, systemic al)s()rpti()11
`is lttf)(1(‘iC(1 as 21 I'11‘st~01‘(1c1' p1'(>(:css. \/Vhen it is 7,910 ()1'(l(.*1', the ('qt1ati()11s St|i)S(‘(]ll(T11li)’
`(i(.‘\’(‘i()[)(’(1 i11 (‘.l1aptc1'9 apply.
`
`EXPOSURE-TIME AND EXPOSURE—DOSE RELATIONSHIPS
`
`Thesyste111it:expost11‘c to‘.1(l1‘11gat'tcé1".1single (‘Xll'2lV}lS(‘l1i'«lt‘ (lost: rlcrpcnrls on both sys-
`tt.-mic 21l)s<>1'ptim1 a11d(lisp<>sitio11. (J<msi(lc1‘ first how cxposttrv with time ai'tc1".111 cxt1".1—
`\r;1st'11la1' (lose c'<>111pa1'c=s with that seen 211101‘ an i11t1".1ve11o11s (lose.
`
`Extravascular versus Intravenous Administration
`
`r’\i):so1'ptio11 delays and 1'c(i11<'cs the 11121g11it11(lc:oi'peak plasma concentration (‘()l1t1')al'(Y(i
`with that scent z1['tc*1' an vqual it1t1ave11(>t1s bolus (i()SL‘. Thtrsc <>t‘['c(‘ts are p<>1't1'21yc(l for
`a.-;pi1'in in Fig. (3-3.
`The liS(’ and tall (tithe drug (‘()I1C(fI|ll'2lIi()Il i11 plasitta 211101‘ t‘Xll'21\'2l.S‘(‘tti&ll' 21<h11i11is—
`t1‘21tim1 are best 1111tlc1'stoo(,l by rca|iI.i11g that at any time.
`
`Iftilra of
`('/1(1'21,gr< Q/' =
`(lr1.4.g' in /)0/ly
`
`Kn - /M —
`Rate of
`21l)so1'pti()11
`
`/1' - A
`Rate of
`oli111i11atj<m
`
`liq. (3 -3
`
`|nnoPharma Exhibit 1024.0006
`
`

`

`CHAPTER 6 I Extravascular Dose and Systemic Absorption
`
`109
`
`10
`
`8
`
`6
`
`’_T
`?»
`E 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 pM). (Modifledfrom the
`data of Rowland M, Riegelman S, Harris PA,
`et al. Absorption kinetics ofaspirin in man fol-
`lowing oral administration ofan aqueous solu-
`tion. J Pharm Sci 7972;67:379-385. Adapted
`with permission of the copyright owner.)
`
`0
`
`20
`
`40
`
`60
`Minutes
`
`80
`
`100
`
`120
`
`The schcine in Fig. 6-4 illustrates the €X])(‘Clklll()l'1. Drug is input into the reservoir
`by :1 lirst—or<le1' process and is CliI1lll]d[C(l iii the saine nl21l11lC1'£1S tl'12itfoll()wir1g21r1 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‘z1l)sorption is inaximal and rate ofeliininzltion is zero. Therefore, as
`drug is 2il)sorbe(l, its rate ol'21l)sorptio11 decreases, whereas as concentration in the reser-
`voir rises, its rate ofeliiniiizition increases. Consequently, the (li{l'erence between the two
`rates diminishes. As long as the rzite ofahsorption exceeds that ofeliniination the con-
`centration in the reservoir continues to rise. Eventually, 21 time, tum, is re2tc.hed when the
`rate ofeliniinzition niutclies the rate of absorption; the concentration is then at 21 maxi-
`mum, (.‘"m_\_. Subsequently, the rate ofelimination exceeds the rate of absorption and the
`coiicentmtion declines, as shown in Fig.
`for the plasnia (‘.()l1(i(;‘11LI‘21ti()l'1 ofzispirin after
`21 single oral dose.
`
`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. 53) de-
`pends on the extent of its tissue distribution
`(volume of reservoir, V), and how well the drug
`inséixtracted from the fluid going to the gum.
`_
`“lg W83” (5) (as measured by CL). In this
`mtegiated 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
`reservoir.
`
`|nnoPharma Exhibit 1024.000?
`
`
`
`Extractor
`
`‘
`
`Fraction extracted during
`passage through extractor, E
`
`
`
`InputRate
`
`Time
`
`Reservoir
`
`

`

`1 10
`
`SECTION II I Exposure and Response After a Single Dose
`
`The peak plasma concentration following extravascular administration is lower
`than the initial value following an equal intravenous bol11s (lose. In the former case, at
`the peak time some drug remains at the absorption site and some l1as already been elim\
`inated, while the entire dose is in the body immediately following the intravenous dose,
`Beyond tl1e peak time, the plasma concentration exceeds that following intravenous
`a(ln1inistration 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 a(lministration 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 ofelimt
`ination is:
`
`Rate ofelimination = CI,-(}
`
`Eq. 6-4
`
`Integrating over all time,
`
`Total amount eliminated = C[.° AUC
`
`Eq. 6-5
`
`The total amount eliminated after an oral dose equals the total amount absorbed,
`F‘ Dose, where the parameter 1', bioavailability, takes into account that only this frac~
`tion of the oral dose reaches the systemic circulation. That is,
`
`F - I)osze
`Total amount
`absorbed
`
`=
`
`C1. - 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 (lose 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,
`
`I)().s'L',«,, = Cl(:(mm(X:'AUC,-,,
`
`Eq. 6-7
`
`After an extravascular (ev) close,
`
`If,, -1)o.s‘(a,,, = (ilmm-nar 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", = ”“"“)
`
`"V
`
`/lUC,,,
`
`I)0.s‘(€,.,,
`
`Eq. 6-9
`
`|nnoPharma Exhibit 1024.0008
`
`

`

`CHAPTER 6 I Extravascular Dose and Systemic Absorption
`
`1 11
`
`For example, if tl1e aI'ea rati() for the same dose administered orally an(l intravenously is
`0.5, only 50% of the oral dose must have been al)sorbed 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 ofadministration, 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,
`
`F,‘ ' Dose,‘
`Total amount
`absorbed
`
`= (lltaarrum? ' AUCA
`Total amount
`eliminated
`
`F,, - I)0se,,
`Total amount
`absorbed
`
`= Clea'r(m(:e - A UCB
`Total amount
`eliminated
`
`Eq. 6-10
`
`Eq‘ 6.11
`
`AUC ,
`"
`Relalivza biorm/ulzz,/)zl1.l I = (
`‘
`9
`g A U(,,,
`
`_
`
`.
`
`,
`
`Dose
`"
`I)0.s‘eA
`
`E . 6-12
`‘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-ti1ne 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 (lose absorbed produces a proportional lncrease in plasma concentra-
`tion at all times. The value of tum remains unchanged, but (rum and AUC increase pro-
`portionally with (lose.
`
`Changing Absorption Kinetics
`
`Alterations in absorption kinetics, l'or.examp'le, by changing dosage form‘ 01, giving the
`product with food, produce changes m the time profiles of the plasma concentration.
`This point is illustrated by the three situations depicted in the semilogarithmic plots of
`Fig. ('3-5 involving only a change in the absorption half-life. All other factors (extent of
`
`|nnoPharma 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)
`
`:3
`
`o_o1
`
`0
`
`10
`
`
`
`PlasmaDrugConcentration(mglL) P
`
`O 01
`
`O
`
`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 so 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.
`
`|nnoPharma Exhibit 1024.001O
`
`

`

`CHAPTER 6 I Extravascular Dose and Systemic Absorption
`
`113
`
`absorption, clearance, and volume ofdistribution a11(l hence elimination l1ali'—liI'e) re-
`niaiii unchanged.
`
`Disposition is Rate Limiting
`
`hi Case A, the most eoinmon situation, absorption hall‘-life is much shoi'tei' than
`elimination liallllife. In this case, most of the drug has been absorbed an(l little has been
`eliminated by the time the peak is reached. Tl1erea['t'er, decline of drug is determined
`primarily by the disposition ofthe drug, that is, disposition is the rate—limiting step. The
`half-life estimated from the decline phase is therefore the eli1ni1- ition l1all’—life.
`In Case R, absorption halI‘—lii‘e is longer than in Case A but still sliorter than eli1ni-
`nation liztlillife. The peak occurs later (I'M increased) because it takes longer for the
`concentration to reach the value at which rate of elimination matches rate ofabsorp--
`tion; the (Ilm, is lower because less drug has been absorbed by that time. liven so, ‘.ibsoi'p-
`tion is still essentially complete before the majority of drug has been eliminated.
`Consequently, disposition remains the rate-limiting step, and the terininal decline still
`reflects the eliininatioii l1alf—li{'e.
`
`Absorption is Rate Limiting
`
`Occasionally, al’>sorption half—life is longer than elimination liallllife, and (Jase C prevails
`(Fig. (3-5) . The peak C()l'1C€l1[F21I'lOI1 occurs later yet and is lower than in the two previous
`cases, reflecting the slower absorption process. Again, (hiring the rise to the peak, the
`rate of elimination increases and eventually, at the peak equals the rate of absorption.
`However, in contrast to the previous situations, absorption is now so slow that eoi1sider—
`able drug reinains to be absorbed well beyond the peak time. Furtherinore, 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 rate-limiting step. Under these circiiinstances, since
`the rate ofelimination essentially matches the rate ol'absorption, the following approx-
`imation (z) can be writtien:
`
`N
`
`k - A
`Rate of
`
`lea ~ A11.
`Rate of
`
`elimination
`
`absorption
`
`That is,
`
`A
`
`z
`
`t
`
`in )
`
`/
`Ira
`—k— ‘Ar;
`Amount
`.
`.
`
`remaining to
`
`'
`be absorbed
`
`1<jq_ (3.13
`
`‘
`‘
`].,]'(,_]41.
`
`Accordingly, the plasma concentration (C = /l/V) (hiring the decline phase is
`directly proportional to the amount reinaining to be absorbed. For example, when the
`amount remaining to be absorbed falls by one-half so does the plasma c(mCenmm0n.
`The time required for this to occur is the absorption lialf-life. That is, the half—1i{'e of
`decline of drug in the body now corresponds to the absorption lizillllife. Flip
`-flop is a
`common descriptor for this kinetic situation. When it oec
`iirs, the terms absorption
`
`|nnoPharma Exhibit 1024.0011
`
`

`

`1 14
`
`SECTION II I Exposure and Response After a Single D059
`
`phase and elimination phase for the regions where the plasma coneentratioii—t1nie euwe
`rises and falls, respectively, are clearly misleading.
`
`Distinguishing Between Absorption and Disposition Rate Limitations
`Although (lisposition generally is rate-liiniting, the preceding (liscussi()i’i suggests that catt-
`tion sliould be exercised in interpreting the meaning of lléll-l-life‘ (lete.rin1n.c‘d from tll-C
`decline phase following extravascular administratioii. Confusion is avoided if the drug is
`also given intravenously. In practice, however, intravenous dosage Iorms ol many drugs
`do not exist for clinical use. Absorption and disposition rate limitations may be distin-
`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 concentration difference between the diffusible unbound con-
`centrations at the absorption site and in systemic blood. The coticeiitratioit gradient
`across the gastrointestinal absorptive membranes is maintained by distribution to tis-
`sues and elimination of absorbed drug. Physiologic and physical factors that deterlninc
`movement of drug through ineinbran es in general are discussed in Chapter 4. Included
`among them were the physicoehemical 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 tlirotigh the membranes dividing the absorption
`site from the blood, it must be in solution. Most drugs are administered as solid prepa-
`rations. Common examples are tablets and capsules. Before addressing the issues ii1volv-
`ing drttg release from a solid dosage form, let us first consider the events that result in
`systemic absorption after oral administration of a drug in solittion.
`
`Gastrointestinal Absorption
`
`In accordance with the prediction of the pH partition hypothesis, weak acids are ab-
`sorbed more rapidly from the stomach at pH l.() 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 aii(l, 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 M2, and an estimated 1 L of blood passes through the intestinal capillaries each
`mintite. The corresponding estimates for the stotnach are only I M‘-’ and 150 nil./inin.
`The permeability 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 coin-
`perisate for the decreased fraction ofun-ionized acid in the intestine. Indee(l, the absorp-
`tion of allcompounds——acids, bases, and neutral compot1iids—is faster from the (small)
`intestine than from the stomach. Because absorption is greater in the small intestine, the
`rate of gastric emptying is a controlling step in the speed of drug absorption.
`
`|nnoPharma 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/antipyrctic.
`Retention of acetaminophen in tlie 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 l‘1igher 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 microflora. The mean pH, 6.6, iii the proximal small
`intestine rises to 7.5 in the terminal ileum, and then falls sharply to 6.4 at the start of the
`cec11m 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 (P - SA) tends to decrease progressively from
`duodenum to colon. This applies to all drug molecules traversing the intestine epithe-
`lium by non—carrier-mediated processes, wl1etl1er via the transcellular (through 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 cecum as reflected by the reduced AUC (Fig. 6—7A).
`
`
`
`PlasmaAcetaminophen
`
`(mg/L)
`Concentration
`
`Slowing gastric emptying
`FIGURE.
`by propantheline (30 mg intravenous) slows the
`rate ofabsorption of acetaminophen (1 500-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 (
`Mete-
`clopramide (10 mg intravenous), which short-
`ens the time for gastric emptying, hastens the
`absorption of acetaminophen (- - -). (Redrawn
`from N/mmo 1, Heading RC, Tothill P, et al.
`Pharmacological modification ofgastric emp-
`Wing-' effects ofpropantheline and metoclo-
`pramlde on paracetamol (acetaminophen)
`absorpt/on. Br Med] 7973; 7587-588.)
`
`|nnoPharma Exhibit 10240013
`
`

`

`1 16
`
`SECTION II I E><po5I.n‘e and Response After a Single DOSE
`
`B
`
`3 1000
`2 F»
`gé
`5.5
`n: 1;
`E‘?
`In 3
`2 5
`0
`
`1” o”'""""”''I'“"””§”'—'"72
`Hours
`
`2
`
`"
`
`A
`
`3 son.
`gs. 400
`72 5,
`'5 g 300
`'1 ‘E
`E; 200
`3 2.
`E 5 100
`0
`
`°
`
`
`
`lion rs
`
`The g-’I3i.i1)il\l€-‘-3T.iIlillF1lJSY)ipti()iIL)ilaiiltitlllle varies with site of appli.r.ati0ii.ihe variation is shown in linear
`FIGURE 5-7
`(A) and serriilug»riii.lirriir. (B) plots of the rrrean p|.asi‘na U)iI',P_|Il|aliL)Ii~tliTl€‘ profiles of rarritirlirre rihseivwi after placing
`an aqiie-Otis soiiitioi. (6 mi) rjgntaiiiing '1soirrgmfrarriticlirie hydrochloride intotlre stomach (O),jejunurn (A), and colon
`(ll) of eight VOlLli‘It"€'ElS via a I1€iS'.)9ill'F.‘l
`ic liuhe. i he rnncli less exterrsive absr_)ipti0r'i of this siriall (MW : 3'13 g/mol) polar
`r‘IiDl@(.I'.ll‘.-‘.‘ from the uilorr i