`
`third edition
`
`Clinical Pharmacokinetics
`
`
`
`MALcoiM ROWLAND
`: THOMAS M. tozcn
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`' MYLAN PHARMS. INC. EXHIBIT 1022 PAGE 1
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`MYLAN PHARMS. INC. EXHIBIT 1022 PAGE 1
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`4
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`EXTRAVASCULAR DOSE
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`OBJECTIVES
`
`The reader will be able to:
`l . Describe the characteristics of, and the differences between, first-order and zero-order ab(cid:173)
`sorption processes .
`
`2. Determine w hether absorption or disposition rate limits drug elimi nation, given plasma con(cid:173)
`centration-time data following different dosage forms or routes of administration.
`
`3. Anticipate the effect of altering rate of absorption , extent of absorption , clearance, or volume
`of distribution on the plasma concentration and amount of drug in the body following extra(cid:173)
`vascular administration.
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`4. Estimate the bioavailability of a drug, given ei ther plasma concentration or urinary excretion
`data following both extravascular and intravascular administration.
`
`5 . Estimate the relative bioavailability of a drug , given either plasma concentration or urinary
`excretion data following different dosage forms or routes of administration .
`
`6. Estimate the renal clearance of a drug from plasma concentration and urinary excretion
`data following extravascular administration.
`
`For systemically acting drugs , absorption is a prerequisite for therapeutic activity when
`they are administered extravascularly. The factors that influence drug absorption are con(cid:173)
`sidered in Chap. 9, Absorption. In this chapter the following aspects are examined: the
`impact of rate and extent of absorption on both plasma concentration and amount of drug
`in the body; the effect of alterations in absorption and disposition on body level-time
`relationships; and the methods used to assess pharmacokinetic parameters from plasma
`and urinary data following extravascular administration.
`The term bioavailability is commonly applied to both rate and extent of drug input into
`the systemic circulation. Throughout this book the term will be limited to the extent of
`drug input and can be considered as the fraction, or percent, of the administered dose
`absorbed intact.
`
`KINETICS OF ABSORPTION
`
`The oral absorption of drugs often approximates first-order kinetics, especialiy when given
`in solution. The same holds true for the absorption of drugs from many other extravascular
`sites including subcutaneous tissue and muscle. Under these circumstances, absorption is
`characterized by an absorption rate constant, ka , and a corresponding half-life. The half(cid:173)
`lives for the absorption of drugs administered orally in solution or in a rapidly disintegrating
`dosage form usually range from 15 min to 1 hr. Occasionally, they are longer.
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`34
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`38
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`EXTRAVASCUlAR DOSE
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`CHAPTER 4
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`absorption half-life. All other factors (bioavailability, clearance, and volume of dist1ibution
`and hence elimination half-life) remain constant.
`In Case A, the most common situation, absorption half-life is much shorter than elim(cid:173)
`ination half-life. In this case, by the time the peak is reached, most of the drug has been
`absorbed and little has been eliminated. Thereafter, decline of drug in the body is deter(cid:173)
`mined primarily by the disposition of the dr g, that is, disposition is the rate-limiting step.
`The half-life estimated from the decline pha e is, therefore, the elimination half-life.
`In Case B, absorption half-life is longer tha in Case A but still shorter than elimination
`longer for the amount in the body to reach
`half-life. The peak occurs later because it tak
`the value at which rate of elimination matche rate of absorption; the Gnun is lower because
`less drug has been absorbed by that time. Even so, absorption is still essentially complete
`before the majo1ity of drug has been eliminated. Consequently, disposition remains the
`rate-limiting step, and the terminal half-life remains the elimination half-life.
`
`Absorption Rate-Limited Elimination
`
`Occasionally, absorption half-life is much longer than elimination half-life, and Case C
`prevails (Fig. 4-3). The peak occurs later and is lower than in the two previous cases. The
`half-life of decline of drug in the body now corresponds to the absorption half-life. During
`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 so slow
`that much of the drug remains to be absorbed well beyond the peak time. The drug is
`either at the absorption site or has been eliminated; little is in the body. In fact, during the
`decline phase, the drug is eliminated as fast as it is absorbed. Absorption is now the rate(cid:173)
`limiting step. Under these circumstances, since the rate of elimination essentially matches
`the rate of absorption, the following approximation ( =) can be w1itten
`
`that is,
`
`=
`
`k · A
`Rate of
`elimination
`
`ka · Ao
`Rate of
`absorption
`
`k ) Amount
`..
`a
`moun
`A
`t
`in bod = T · remaining to
`(
`Y
`be absorbed
`
`4
`
`5
`
`Accordingly, amount in the body (and plasma concentration) during the decline phase
`is directly proportional to the amount remaining to be absorbed. For example, when
`amount remaining to be absorbed falls by one-half, so does amount in body. However, the
`time for this to occur is the absorption half-life.
`Absorption influences the kinetics of drug in the body; but what of the AUG? Because
`bioavailability and clearance were held constant, it follows from Eq. 3 that the AUG must
`be the same for Cases A, B, and C.
`
`Distinguishing Absorption From Disposition Rate-Limited Elimination
`
`Although disposition generally is rate-limiting, the preceding discussion suggests that cau(cid:173)
`tion may need to be exercised in interpreting the meaning of half-life determined from the
`decline phase following extravascular administration. Confusion is avoided if the drug is
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`MYLAN PHARMS. INC. EXHIBIT 1022 PAGE 15
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`48
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`Table 4-4.a
`
`TIME
`I min)
`
`0
`10
`20
`30
`40
`50
`60
`90
`120
`150
`180
`210
`240
`360
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`EXTRAVASCUlAR DOSE
`
`CHAPTER 4
`
`PLASMA ACETAMINOPHEN CONCENTRATION
`lmg/L)b
`
`SUBJECTS
`STANDING
`
`0
`2 l
`5.6
`5 8
`6.3
`4.7
`4.1
`3 .5
`2.8
`2.2
`1.7
`l 8
`1.5
`0.75
`
`SUBJECTS
`LYING DOWN
`0
`0.1
`0.3
`l.l
`1.9
`2 8
`3 2
`3.9
`3 l
`29
`1.8
`l .7
`1.5
`0.7
`
`0 Abstracted from Channer, K.S. and Roberts, CJC EHect of delayed esophagea l transrt on aceta minophen absorption. Cl in. Pharmacol. Ther , 3772-
`76, 1985
`bone mg/l = 6.6 µM
`
`a. What effect does delayed esophageal transit have on the speed and extent of ab(cid:173)
`sorption of acetaminophen?
`b. What process, absorption or disposition , rate-limits the decline in plasma drug con(cid:173)
`centration?
`c. Acetaminophen is used for the relief of pain. Do the findings of this study affect
`the recommendation for the use of this drug?
`6. Beshyah et al. (Beshyah, S.A. , Anyaoku, V , Niththyananthan, R , Sharp, P,, and John(cid:173)
`ston, D.G.: The effect of subcutaneous injection site on absorption of human growth
`hormone: Abdomen versus thigh. Clin. Endocrinol. , 35:409-412, 1991 ) examined the
`effect of s.c. injection site on the absorption of human growth hormone. Table 4-5
`lists the mean serum concentrations in 11 subjects observed during the first 12 hr after
`the administration of 4 IU (international units ) of biosynthetic human growth hormone.
`The drug was injected, on separate occasions, into a lifted fold of skin on the anterior
`thigh and a lowe r quadrant of the abdomen.
`
`Table 4-5. Mean Serum Concentrations of Growth Hormone for 1 2 hr following
`s.c. lniection of 4 IU in the Abdomen and Thigh
`
`TIME lhr)
`INJECTION SITE
`
`Abdomen
`Thigh
`
`0
`
`<2
`<2
`
`2
`
`3
`
`34
`16
`
`55
`27
`
`92
`27
`
`8
`7
`6
`5
`4
`SERUM CONCENTRATION lmrlliunr ts/l)
`74
`51
`23
`28
`
`84
`37
`
`75
`28
`
`9
`
`10
`
`11
`
`24
`19
`
`20
`14
`
`12
`12
`
`12
`
`8
`10
`
`31
`20
`
`a. Is the re information in these data, gleaned fron~ graphical analysis, to suggest
`whether absorption or disposition of growth hormone rate-limits the terminal de(cid:173)
`cline? Briefly discuss.
`b. Many proteins given subcutaneously or intramuscularly are partially degraded within
`the lymphatic system before reaching the systemic circulation. Calculate the relative
`bioavailability of the drug after s.c. injection into the th igh (relative to abdomen) .
`c. The clearance of growth hormone has been reported in the literature to average
`about 5 Uhr. Roughly estimate the bioavailability of the drug following abdominal
`s.c. injection .
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`MYLAN PHARMS. INC. EXHIBIT 1022 PAGE 25
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`CHAPTER 4
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`EXTRAVASCUlAR DOSE
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`49
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`7. Phe nylethylm alonide (PEMA) is on e of the major metabolites of the antiepileptic drug
`primidone. As part of a program to assess the potential use of PEMA as an antiepileptic
`drug itself, its pharmaco kin etics we re studied following i.v. and oral administration of
`500 mg. Table 4- 6 be low lists the resultant plasma concentrations in one subject. Also,
`81 % of the i.v. dose was recove red in urine unchanged.
`
`Table 4-6. Plasma Concentrations following i.v. and Oral Administration of 500
`mg of PEMA lo a Subject0
`
`TIME [hr)
`
`Plasma concentration
`(mg/LI
`
`0.33
`05
`i.v. 14.7 12.6
`2.4
`oral
`
`0.67
`l 1.0
`
`24
`48
`4
`10
`32
`1.5
`2
`6
`16
`9.0 8.2 79 6.6 6.2 4.6 3.2 2.3 1.2
`3.8 4.2 4.6 8.1 5.8 5 l 4.1 30 2.3 1.3
`
`0 Abstracted from Pisani, F., a nd Richens. A Pharmocokinetrcs of phenylethylmolonamide [PEMAJ after oral and intravenous administration. Cli n. Phor·
`mocokrnet. 8:272-276, 1983
`
`a. From a semilogarithmic plot of the plasma concentrations , estimate the elimination
`half-life of PEMA in th e subj ect.
`b. Calculate the total AUC following i.v. and oral administration.
`c. From the i.v. data, estimate the clearance and volume of distribution of PEMA.
`d . Calculate the oral bioavailability of the drug.
`e. Calculate the renal clearance.
`8. Rowland et al. (Rowland, M., Epstein , W. , and Riegelm an, S.: Absorption kinetics of
`griseofulvin in man. J. Pharm. Sci. , 57:984- 989, 1968) gave griseofulvin orally, 0.5 g of
`a micronized drug formulation and, on another occasion intravenously, 100 mg, to
`volunteers. The plasma concentration-time data obtained in one subject are given in
`Table 4- 7 below.
`
`Table 4-7.
`
`Plasma
`Griseofulvin
`Concentration
`(mg/L)A
`
`ROUTE TIME [hr)
`
`i.v.
`
`0
`
`0
`
`2
`
`3
`
`4
`
`5
`
`7
`
`8
`
`12
`
`24
`
`28
`
`32
`
`35
`
`48
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`I .4 1. I
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`0.98 0.90 0.80
`
`0.68 0.55 0.37
`
`0.24
`
`0. 14
`
`Oro)
`
`0 0.4 0.95
`
`I 15
`
`l 15 1 05 1.2 1.2
`
`0.90 1.05 0.90 0 .85 0.80 0 .50
`
`AOne mg/l = 2 .8 µM
`
`From appropriate plots and calculations, what can be concluded from these data with
`respect to:
`a. Rate of absorption of griseofulvin vvith time on oral administration in this individual?
`b. Completeness of abso111tion ?
`9. Kostenbauder et al. (1975) meas ured plasma ph enytoin concentrations after the ad-
`ministration of sodium phenytoin intramuscularly.(500 mg) and intrave nously (250 ~ ----- _
`The ave rage data obtained in 12 subjects , each of whom received both treatments, are
`listed in Table 4- 8.
`
`Table 4-8 . 0
`
`TIME [hr)
`
`ROUTE
`
`Intramuscula r
`
`0
`
`0
`
`2
`
`4
`
`6
`
`8
`
`12
`
`24
`
`48
`
`3.0
`
`3.2
`
`3.5
`
`3.2
`
`3.6
`
`3.8
`
`4 .1
`
`3.2
`
`72
`
`16
`
`96
`
`0.8
`
`120
`
`0.4
`
`Plasma Phenytoin
`Concentration
`(mg/L)b
`
`Intravenous
`
`56 54
`
`5 2 49
`
`3.9
`
`3.2
`
`2.2
`
`0.88
`
`0.42
`
`0 Abstrocted from Kostenbauder. H.B ., Ropp. R.P, McGovren, JP. Foster , T.S, Perrier, D.G. Blocker.HM., Hulon, W.C. and Kinkel. A.W. Bioovail·
`ability and single-dose phormacokinetics of intramuscular phenytorn. C lrn . Pharmacol. Ther , 18:449-456, I 975
`"one mg/l = 4 . 0 ~1M
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`MYLAN PHARMS. INC. EXHIBIT 1022 PAGE 26
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`EXTRAVASCUlAR DOSE
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`CHAPTER 4
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`a. Estimate the bioavailability of phenytoin from the i.m. site based on area compari(cid:173)
`sons.
`b. From an approp1iate plot of the data , comment on the process limiting the decline
`of the plasma phenytoin concentration following i.m. administration.
`c. Th e authors analyzed the plasma concentration -time data and found that, following
`i.m. administration , 23% of the dose was absorbed within the first hour, and there(cid:173)
`after absorption was much slower. The cumulative abs0111tion data are shown in
`Table 4-9. After the rapid abs0111tion in the first hour, is the subsequent absorption
`better characterized by a zero-order or a first-orde r process?
`
`Table 4-9.
`
`TIME (hr)
`
`Percent of bioovoiloble drug absorbed
`from i.m. site
`
`23
`
`6
`
`40
`
`19
`
`60
`
`40
`
`80
`
`65
`
`90
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`MYLAN PHARMS. INC. EXHIBIT 1022 PAGE 27
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`94
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`MULTIPLE-DOSE REGIMENS
`
`CHAPTER 7
`
`The increased probability of compliance by once daily dosing is countered by kinetic
`argum ents in favor of more frequent dosing. \Vhere the optimum regimen lies depends on
`many factors. For example, for phenobarbital, with a half-life of 4 days, the omission of a
`single daily dose of 90 mg or an 8-hourly dose of 30 mg is of minor importance because
`the average amount in the body at steady state is 556 mg (see Fig. 7-5). Thus, the smaller
`the ratio of the dosing interval to half-life, the less the kinetic impact of a missed dose.
`Other determinants of the optimal regimen include factors such as those affecting the
`likelihood of compliance (seve1ity and nature of disease, occupation of patient, personality
`of patient) and those relating to the pharmacodynamic characteristics of the drug (steepness
`of concentration-response curves, width of therapeutic window).
`
`PRACTICAL ASPECTS OF MULTIPLE-DOSE ADMINISTRATION
`
`So far, consideration has been given primarily to the amount of drug in the body following
`multiple i.v. bolus injections , or their equivalent, at equally spaced intervals. In practice,
`chronic administration is usually by the oral route . F urthermore, only drug concentration
`in plasma or in blood can be measured and not amount of drug in the body. These aspects
`are now considered. Problems related to unequal doses and dosing intervals and to missed
`doses are covered in Chap. 18, Concentration Monitoring.
`
`Extravascular Administration
`
`The oral (also intramuscular [i.m. J, buccal, subcutaneous [s .c.J, and rectal) administration
`of drugs requires an added step , absorption. Eqs . l to 4 apply to extravascular administra(cid:173)
`tion, provided that absorption has essentially ended within a small fraction of a dosing
`interval, a condition similar to i.v. bolus administration. Even so, a correction must be made
`if bioavailability is less than l. When absorption continues throughout a dosing interval, or
`longer, then the relationships of Eqs. I and 8 still apply. These relationships allow esti(cid:173)
`mation of the average plateau amount in the body and the average plateau concentration,
`respectively. The slowness of drug absorption affects the degree of fluctuation around, but
`not the value of, the average concentration. The exception is when absorption becomes so
`slow that there is insufficient time fo r complete absorption, e.g., when limited by the transit
`time within the gastrointestinal tract.
`The therapeutic impact of differences in absorption kinetics, but not in bioavailability,
`of extravascularly administered drug products given repeatedly depends on the frequency
`of their administration. As illustrated in Fig. 7- 7, major differences seen following a single
`dose only persist and are of potential therapeutic concern at plateau when the drug products
`are given infrequently, relative to the half-life of the drug. Differences between them
`almost disappear at plateau when the products are give n frequently. In the latter case, as
`stated previously, with extensive accumulation of drug, the concentration at plateau is
`relatively insensitive to variations in absorption rate.
`
`Plasma Concentration Versus Amount in Body
`
`During multiple dosing, the plasma concentration can be calculated at any time by dividing
`the corresponding equations defining amount by volume of distribution. Distribution equi(cid:173)
`librium between drug in the tissues and that in plasma takes time. Thus, observed maximum
`concentrations may be appreciably greater than those calculated by dividing Eqs. l and 3
`by V (see Chap. 19).
`The average plateau concentration may be calculated using Eq. 8. This equation is
`applicable to any route, method of administration, or dosage form, as long as bioavailability
`and clearance remain coµstant with both time and dose.
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`MYLAN PHARMS. INC. EXHIBIT 1022 PAGE 39
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`104
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`MULTIPLEDOSE REGIMENS
`
`CHAPTER 7
`
`a. Given that absorption is instantaneous relative to elimination, calculate the following
`when a 50-mg dose of chlorthalidone is taken daily at breakfast
`1. The maximum and minimum amounts of drug in the body at plateau
`2. The accumulation ratio
`3. The minimum plasma concentration at plateau
`4. The time required to achieve 50% of plateau
`b. Complete the table below for the dosage regimen of chlo1thalidone given in (a).
`
`Dose
`
`2
`
`Amounl of Chlor1holidone in Body lmg)
`5
`
`4
`
`3
`
`6
`
`7
`
`c. Prepare a sketch on regular graph paper of th e amount of chlorthalidone in the
`body with time. Show the salient features of accumulation of this drug during
`therapy.
`d. If required, what is the loading dose of chlorthalidone needed to immediately attain
`the condition at plateau?
`4. Mr. J.M., a nonsmoking 60-kg patient with chronic obstructive pulmonary disease, is
`to be started on an oral regimen of aminophylline (85% of which is theophylline). The
`pharmacokinetics parameter values for a typical patient population with this disease
`are:
`
`F = 1 .0 (for theophylline)
`v = 0 .5 L/kg
`CL = 40 ml/hr /kg
`
`D esign an oral dosage regimen of aminophyllirie (100- and 200-mg tablets are mar(cid:173)
`keted) for this patient to attain and maintain a plasma concentration within the ther(cid:173)
`apeutic window, 10 to 20 mg!L. The absorption of theophylline is complete an d rapid.
`5. Table 7- 7 lists a typical plasma concentration-time profile obtained following an oral
`500-mg dose of a drug. The AUC is 80.6 mg-hr/L, and the terminal half- life is 5 hr.
`
`Table 7-7.
`
`Time (hr)
`
`Plasma drug
`concen tratio n (mg/L)
`
`0
`
`0
`
`2
`
`4
`
`8
`
`12
`
`24
`
`36
`
`48
`
`2 3
`
`47
`
`5 2
`
`4.0
`
`2 8
`
`06
`
`0 14
`
`0 03
`
`a. vVhat oral dosing rate of drug is needed to maintain an average plateau concentration
`of 10 mg/L?
`b. The decision has been made to give the drug once every 12 hr. What is:
`l. The unit dose strength of product needed?
`2. The plateau trough concentration expected?
`6. The therapeutic dose of a rapidly (compared to elimination ) and completely absorbed
`drug is 50 mg. A controlled-release dosage form to be given every 8 hr is designed to
`release its contents evenly and completely (no loading dose) over this dosing interval.
`t-1-.a ].., ., tf J; f~ ~ f <-h ~ ;i_,,_ : ~ A
`l:i".a n
`1- J,0 t
`1.... ••
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`MYLAN PHARMS. INC. EXHIBIT 1022 PAGE 49
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`CHAPTER 7
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`MULTIPLE-DOSE REGIMENS
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`105
`
`b. To achieve a prompt effect, a rapidly absorbed dosage form is administered initially.
`When should the first controlled-release dosage form be given?
`c. Following the dosage regimen in (b) what is the total dose (i) for day 1? (ii) for day
`2?
`d. In tabular form or on the same graph, provide the relative amounts of drug in the
`body versus time curves expected when the controlled-release preparation only is
`given (i) every 4 hr (ii) every 8 hr (iii) every 12 hr.
`7. Adinazolam is a drug under investigation for the treatment of depression and panic
`disorders. Table 7-8 summarizes some of the salient pharmacokinetic information fol(cid:173)
`lowing single and multiple doses of immediate-release and controlled-release products .
`
`Table 7-8. Mean Adinazolam Pharmacokinetic Information Following Single and
`Multiple Doses of Immediate-Release and Controlled-Release Preparations to a
`Group of 1 6 Subiectsa
`
`IMMEDIATE RELEASE
`
`CONTROLLED RELEASE
`
`SINGLE DOSE
`40 mg
`0.57b
`0.15
`l.00
`2 20
`
`MULTIPLE DOSES
`40 mg every B hr
`l 72 c
`0.20
`
`AUC (mg-hr/LI
`Cmax (mg/LI
`T max (hr)
`Terminal t112 (hr)
`0 Abstracted from Fleishalker, J.C and Wright, CE. Pharmocakinelic and pharmacadynam 1c comparison of 1mmediote-releose and suslarned-releose
`od1nazolam mesylate tabrets after singe-dose and multiple-dose adm inistra tion Pharm Res. 9· 457-462 1992
`bAUC [0->o)
`cAUC [0-24) after 7 days of dosing
`
`SINGLE DOSE
`60 mg
`0 88b
`007
`2.50
`5.50
`
`MULTIPLE DOSES
`60 mg every l 2 hr
`] _57c
`0 11
`
`a. What rate-limits the decline of plasma adinazolam concentration following the ad(cid:173)
`ministration of the controlled-release product?
`b. On multiple dosing, have the immediate-release and controlled-release products
`been given long enough to ensure that a plateau shou ld have been reached? In your
`answer, indicate whether any diffe rence is expected in the time to reach plateau
`between the two products.
`c. For both products , are the plasma concentration data obse rved on multiple dosing
`(Table 7- 8) those predicted from single-dose data?
`d. What is the relative bioavailability of adinazolam of the con trolled-release product
`compared to the immediate- release product?
`e. Are the pharmacokinetics of adinazolam after administration of the immediate-re(cid:173)
`lease and the controlled-release products such that the terminal half-life can be
`determined within the respective dosing inte rvals at plateau?
`f. What are the degrees of accumulation associated with the immediate-release and
`the controlled-release regimens given that the AUC(O to 8 hr) and AUC(O to 12 hr)
`following the single 40-mg immediate-release product and the 60-mg controlled(cid:173)
`release products are 0.45 and 0.44 mg-hr/L, respectively? Base yo ur calculations on
`A UC considerations.
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`MYLAN PHARMS. INC. EXHIBIT 1022 PAGE 50
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