Selection of a slow-release theophylline product
`
`\ L
`
`eslie Hendeles, Pharm.D., and Miles Weinberger, M.D.
`Gainesville. F1a.. and Iowa City. Iowa
`
`Slow-release formulations of theophylline. if absorbed completely. consistently, and at a
`sufiiciently slow rate. provide more stable serum concentrations at longer dosing intervals than
`plain uncoated tablets or liquids and thus have the potential to improve efficacy.
`.
`compliance. However. clinically important differences in extent and rate of absorption exist
`among the 15 slow-release formations available under 29 different brand names or as generic
`products in the United States. Moreover. food has different effects on the various formulations,
`Whereas some formulations are little affected by food with only a slight delay in absorption,
`others undergo malabsorption in either the presence or absence offood, depending on as yet
`unidentified but specificformulation factors, Because fluctuations in serum concentrations at any
`selected dosing interval are a function of the rate of elimination of theophylline from the
`patient and the rate of absorption of theophyllinefrom theformulation. selection of a product
`and dosing interval needs to be an individuali:
`ed clinical decision independent of marketing or
`regulatory influences. Most formulations with c
`[aims for mice-daily dosing cannot reliably
`maintain fluctuations in serum concentration w
`hereby the peak will not exceed twice the trough.
`Moreover. of the three products approved for once—a-day dosing. fluctuations in serum
`concentration are more likely to be larger than are clinically optimal, and malabsorption occurs
`with two of the three approvedformulations unless taken after food: one. in fact. has such a
`large increase in rate and extent of absorption is
`'hen taken with food that its postprandial
`absorption characteristics are aptly described as
`“dose-dumping," (J ALLERGY CLIN IMMUNOL
`1986;78:743-51.)
`
`Until the late 19705, Goodman and Gilman’s The
`Pharmacological Basis ofTherapeutics. the American
`Medical Association's Drug Evaluations. and other
`authoritative references stated that “theophylline was
`erratically and incompletely absorbed." They quoted
`a study published in I950 that demonstrated incom-
`plete absorption from enteric-coatcd tablets and sup-
`positories, but this study actually indicated'no evi-
`dence of a bioavailability problem with plain uncoated
`tablets.‘ Subsequently absolute bioavailability studies
`have demonstrated that theophylline is rapidly, com—
`pletely, and consistently absorbed from formulations
`that rapidly release the drug.” 3
`Rapid-release formulations, however, can result in
`excessive serum concentration fluctuations. particu—
`larly in patients with rapid elimination." 5 There are
`three possible solutions to this problem. First.
`the
`
`From the Division of Clinical Pharmacokinetics. College of Phar-
`macy, and Division of Clinical Pharmacology. Department of
`Pediatrics, The University of Florida, Gainesvillc. Fla. and the
`Pediatric Allergy and Pulmonary Division. The University of
`Iowa. Iowa City. Iowa.
`Reprint requests: Leslie Hendeles. PharmD. , l. Hillis Miller Health
`Center. Box 1486. University of Florida. Gainesville. FL 32610.
`
`Abbreviations used
`Elimination half-life
`
`Volume of distribution
`
`dosing interval can be shortened to 4 to 6 hours. but
`this is incompatible with a normal life-style. Second.
`a drug such as cimctidine could be given to inhibit
`theophylline metabolism, but this is an inappropriate
`method of dealing with the problem because it places
`the patient at risk of toxicity from the second drug.
`The third and only practical method of reducing fluc-
`tuations is to decrease the rate of absorption of the
`formulation." °
`
`At least one clinical study7 has demonstrated that
`slow-release formulations offer
`the potential
`for
`greater efficacy and improved compliance. Among 35
`children with chronic asthma randomly assigned in a
`crossover manner to receive a rapid—release product
`given every 6 hours and a slow—release formulation
`twice a day, at the same total daily dose. the percent
`of days totally free of wheezing was significantly
`greater during use of the slow—release formulation
`compared with the rapid-release formulation. More-
`
`743
`
`SHIRE EX. 2037
`KVK v. SHIRE
`IPR2018—00290
`
`Page 1
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`

`Fraction Absorbed
`1 O
`
`
`
`
`
`O
`
`2
`
`4
`
`I
`
`i
`8
`
`6
`
`( L_‘L
`L
`12
`14
`10
`Time (hours)
`
`16
`
`i
`l
`.
`l
`l
`l
`i
`18 20 22 24
`
`9 B7 6 5
`
`1 0
`
`‘
`
`I Plain Tablets
`U Theo my 200 300
`. Puyiioconim
`O Slo pnyilin Giroeaps
`A Theolair SR
`
`4 .
`3
`2
`
`FIG. 1. Rate and completeness of absorption of four slow-release theophylline formulations and
`plain uncoated tablets. Each determination of cumulative fraction absorbed represents mean of
`values calculated from sequentially measured serum concentrations after administration of
`single doses of slow»release product and a rapidly absorbed reference product to adult vol-
`unteers, as previously described.E (From Hendeles L, Weinberger M. Theophylline: a “state of
`the art" review. Pharmacotherapv 198132414.)
`
`over. compliance was significantly higher during the
`slow-release treatment regimen.
`
`METHODS OF EVALUATING PRODUCTS
`
`Slow-release products are formulated in various
`ways to decrease rate of dissolution. the rate-limiting
`step in the absorption process. There are at least 15
`fomtulations available in the United States as 29 dif-
`ferent brands. and some also are sold as generic prod-
`ucts without a brand name. Because manufacturers
`use various methods to formulate their products. many
`of these formulations differ in extent or rate of ab-
`
`sorption.“ “ "
`Two slow—release theophylline products are bio-
`equivalent. and thus can be expected to produce the
`same therapeutic response. when they have the same
`rate and extent of absorption. Extent of absorption can
`be measured when the product in question and a ref-
`erence product. known to be completely absorbed. are
`given in a crossover manner to the same subjects on
`different days. The serum concentration-time curve
`after each product is divided into trapezoids. the area
`of each trapezoid calculated. and the results summed.
`This provides the area under the serum concentration—
`time curve. which is directly proportional
`to the
`amount of drug absorbed into the systemic circulation.
`The actual amount of drug absorbed from the product
`in question. relative to the reference product. is then
`calculated from the ratio of areas under the curves.
`
`In this manner. complete absorption has been docu-
`mented for many slow-release formulations.‘ How-
`ever. incomplete absorption has been demonstrated for
`LaBlD (Norwich Eaton. Norwich. N Y.).‘“ Tcdral—
`SA (Parke-Davis. Morris Plains. N. J.)." Theo-34
`
`(G. D. Searle & Co.. Chicago.
`
`Ill.) (fasting).“‘
`
`‘:
`
`Theo-Dur Sprinkle (Key Pharmaceuticals. Miami.
`Fla.) (after food).”‘ 1‘ Uniphyl (Purdue Frederick.
`Norwalk. Conn.) (fasting).“ and two products av ail-
`able outside the United States. Euphyllin Retard (Byls-
`Guiden. Konstanz. West Germany).” and Theograd
`(Abbott Laboratories. North Chicago. Ill.) (fastingi."‘
`Rate of absorption is determined from the cumu-
`lative fraction of a single dose absorbed over time.‘
`When the various slow-release products are compared
`in this manner. marked differences in rates of ab—
`
`sorption become readily apparent ( Fig. I). Slo-Phyllin
`Gyrocaps (William H. Rorer. Fort Washington. Pa).
`for example. is one of the most rapidly absorbed slow—
`release formulations.“ whereas Theo-24 (taken fast-
`
`its absorption is in-
`ing) is so slowly absorbed that
`complete.” ‘: Once the rate of absorption of a product
`is known. steady-state serum concentrations after mul—
`tiple doses can be predicted. with reasonable accuracy.
`for different dosing intervals. in patients with different
`rates of eliminationL‘ From these data. expected fluc—
`tuations in steady—state serum concentrations can be
`calculated:
`
`Peak — trough
`..
`‘t Fluctuation = —,—-; x
`Trough
`
`(00
`
`Because the width of the It) to 20 ugi‘ml therapeutic
`range is only 10 (Lg/ID]. fluctuations must be <100‘72
`(i.e.. the peak less than twice the trough) to maintain
`serum concentrations within the therapeutic range.
`even when the peak is as high as 20 (Lg/ml. When
`products are compared in this manner it is evident that
`those products with more rapid absorption result in
`serum concentration fluctuations >lOOC/c in patients
`with elimination as rapid as the average child‘s. that
`is. 3.7-hour half-life (Table I).
`
`Page 2
`
`Page 2
`
`

`

`TABLE I. Extent of absorption and predicted fluctuations in serum concentrations during a 12-hour
`dose interval of various slow-release theophylline products
`Extent of
`% Fluctuation'
`absorption
`tla = 7.7 hr
`tr; = 3.7 hr
`Brand name
`Manufacturer
`(%I
`——_—______—__.—_——_
`
`Plain tablets
`Rorer. Johnson &
`Johnson. Riker
`
`Bead-filled capsules
`Central Pharmacal
`
`Cord Laboratories
`
`Graham Laboratories
`
`Key Pharmaceuticals
`K»V Laboratories
`
`Rorer
`Searle
`Slow-release tablets
`Cord Laboratories
`Key Pharmaceuticals
`
`Mead Johnson
`Mundipharma
`Norwich-Eaton
`Parke-Davis
`
`Purdue Frederick
`Riker
`
`Slo-Phyllin, Theophyl,
`Theolair
`
`100
`
`465
`
`125
`
`Physpan
`Quibron-BID
`Theoclear LA
`Theon—300
`Theospan—SR
`Bronkodyl S-R
`SIo—Phyllin Gyrocaps
`Theophyl-SR
`Aerolate
`Somophyllin—CRT
`Theo-Dur Sprinkle
`Elixophyllin SR
`Theobid
`Theovent—LA
`Slo-bid
`Theo- 24
`
`Constant-T
`Theo—Dur 200.300
`TheoDur 100
`Quibron T/SR
`Phyllocontin
`LaBID
`Choledyl SA
`TeoventASR
`
`95
`
`99
`
`I0]
`91/44?
`
`94
`94
`101
`71/100'1'
`
`76
`97
`103
`99
`95
`87
`93
`
`240
`
`230
`
`130
`i
`
`140
`167
`43
`i
`
`155
`39
`88
`128
`165
`252
`154
`
`73
`
`73
`
`47
`i
`
`54
`60
`18
`i
`
`57
`17
`35
`48
`58
`77
`57
`
`'
`
`§
`61/81”
`Uniphyl
`II
`99
`Theolair-SR
`Respbid
`
`§
`II
`
`From Hendelcs L. Weinberger M. J ALLERGY CLtN IMMUNOL 19851762285491,
`‘Percent fluctuation = (Peak — trough serum concentration)/Trough serum concentration x 100: actual fluctuations may somewhatexceed
`predictions because of circadian variation in absorption.“ The ‘1 2 values are the median value for the average child (37 hours) and the
`average nonsmoking adult (7.7 hours), respectively. Predicted fluctuations for the average cigarette smoking adult are similar to those
`for the average child. Fluctuations >100% indicate that peak serum concentrations will be more than double the trough level and thus
`not compatible with maintaining serum concentrations within the therapeutic range even if peak levels as high as 20 ug/ml are attained:
`8-hour intervals are then advisable. regardless of advertising claims for twice-daily or 12-hour dosing. Methodology and validation of
`the derivation of these values have been described.’ ‘
`‘I‘Extent of absorption when taken fasting and with food, respectively
`iBecause rate and completeness of absorption change with food. meaningful predictions of fluctuations cannot be made.
`§Measured fluctuations at steady state with once~daily dosing in subjects with mean ti2 = 8.3 hours were 232% fasting and 109% (range
`22% to 240%) after food.“
`”pH-Dependent dissolution may alter the rate of absorption depending on gastric pH and emptying.’J Therefore. meaningful predictions
`of fluctuations cannot be made.
`
`CLINICAL RELEVANCE OF DIFFERENCES
`BETWEEN PRODUCTS
`lncomplete absorption. If the dose of an incom-
`pletely absorbed product is increased to achieve a se-
`rum concentration within the 10 to 20 ug/ml thera-
`
`utic ran e, lar er doses will be re uired than for a
`1”
`g
`g
`q
`completely absorbed product. If the product is sub-
`sequently given under conditions in which absorption
`becomes complete, or if the regimen is changed to
`the same dose of a completely absorbed oral or intra-
`
`
`
`
`
`Page 3
`
`Page 3
`
`

`

`Serum Theophylline
`lug/ml)
`30
`
`
`
`
`
`25
`
`20
`
`Plant Tablets
`ThaoDur 300
`PM ylloconim
`Slophyllm GyIDCaDS
`Yhaolalr SR
`
`FOOD.
`
`
`
`0123456789101112
`Time(hours)
`
`
`
`FIG. 2. Predicted steady-state serum concentrations for an average child (‘1 2 : 3.7 hours, Vd A 0.5
`L/kg) receiving plain uncoated tablets and four slow-release products in Fig, l at 12-hour dosing
`intervals. The more rapid the rate of absorption, the greater the fluctuations outside the ther-
`apeutic range. Predicted serum concentration fluctuations are 459% for plain tablets, 225% for
`Slo-Phyllin Gyrocaps, 165% for Phyllocontin, (Mundipharma, Limberg Lahn, West Germany),
`149% for Theolair-SR, and 38% for Theo—Dur 300 mg tablets. Predicted fluctuation for SIo-bid
`Gyrocaps (not shown) is 59%. These predictions slightly underestimate actual fluctuations be-
`cause method does not reflect circadian variation in absorption observed for both rapid- and
`slow-release formulations,m Adjusting dose rather than dosing interval will not alter percentage
`fluctuation. Therefore. children, smoking adults, and about 25% of otherwise healthy non-
`smoking adults will generally require 8-hour dosing intervals for most slow-release products,
`for example, those with predicted fluctuations of >100% at ti2 of 3.7 hours.5 (From Weinberger
`M, Hendeles L, Wong L, Vaughan L. Relationship of formation and dosing interval to fluctuation
`of serum theophylline concentration in children with chronic asthma. J Pediatr 1981;99:145.)
`
`in—
`venous formulation, serum concentrations will
`crease. possibly to toxic concentrations. Conversely.
`if the dose initially is adjusted to achieve serum con-
`centrations in the 10 to 20 pig/ml range with a 100%
`absorbed product and the patient subsequently is given
`an incompletely absorbed product. serum concentra—
`tions could decrease to subtherapeutic concentrations
`that might result in exacerbation of asthmatic symp—
`toms, Because of the potential for nonlinear phar-
`macokinetics, a small change in extent of absorption
`is.
`in effect. a change in dose and could result in a
`disproportionate change in serum concentrations.
`These problems could occur without the physician‘s
`awareness if the dispensing pharmacist refills the pre»
`scription with a generic substitute that is absorbed to
`a different extent than the prescribed formulation.
`in
`Diflerenr
`rates of absorption. Fluctuations
`steady-state serum concentrations after multiple doses
`are a function of the rate of absorption of the product.
`the rate of elimination of theophylline from the pa-
`tient. and the dosing interval selected.S All completely
`absorbed products will be associated with relatively
`small fluctuations in serum concentrations if admin-
`
`istered every 12 hours to the average nonsmoking adult
`in whom the median [12 is about 8 hours (Table I). In
`
`fact. in these patients elimination is slow enough. on
`average.
`that serum concentration fluctuations gen-
`erally will be <100‘7c with an inexpensive rapid-rc-
`lease plain uncoated tablet administered every 8
`hours.* However. clinically important differences in
`absorption rates between slow—release theophylline
`products become apparent when steady-state serum
`concentrations are predicted for 12-hour dosing in—
`tervals in patients who metabolize the drug as rapidly
`as does the average child or cigarette—smoking adult
`( Fig. 2).
`Because of differences in rates of absorption. most
`slow-release theophylline products are not
`inter«
`changeable (Fig. 2). Recently. a change in the product
`stocked by the Walter Reed Army Hospital Pharmacy
`to a less expensive generic slow-release theophylline
`resulted in the clinical impression of increased asth—
`matic symptoms or increased side effects among some
`patients.'7 This prompted a controlled study compar—
`ing the same dose of four slow—release formulations
`in 10 patients with asthma in a double-blind crossover
`design. Baker et al. '7 found that the mean theophylline
`concentration for a dosing interval was above or below
`the therapeutic range in 46% of the intervals measured
`on different products whereas this occurred in only
`
`
`
`Page 4
`
`Page 4
`
`

`

`Absorbed
`
`Fraction
`
`Theonur Sprinkle
`n=12 children 16-12 yrs old)
`u Fasting
`
`o Alter Breakfast
`
`
`04812162024253236404448
`Time (hrs)
`(Pederson at al 1984)
`
`10
`
`Fraction
`Absorbed
`
`
`
`Theo-our Tablets
`n=10 adults
`
`
`OFast-ng
`oAtter Breaklast
`
`
`
`
`
` O 3 6 9 12 15 18 21
`24
`27
`30
`
`
`
`Time(hrs)
`(Sips et.al.. 1984)
`
`Fraction
`Absorbed
`
`_/:/I—4;_I/l
`
`Theo-24
`n=8 adults
`a Fasting
`
`(Hendeles et al, 1984)
`
`Time (hrs)
`
`Fractlon
`
`o Alter Breaklast 04812 16 20 24 28 32 36 4O 44 48
`Absorbed
`
`SID-bid
`n=6 adults
`0 Funny
`0 Mia! Breaklast
`
`6
`12
`18
`24
`30
`36
`Time (hrs)
`[Weinberger et, al, 1984)
`
` 0
`
`
`
`FIG. 3. Effect of food on rate and completeness of absorption of four slow-release theophylline
`products. Each determination of cumulative fraction absorbed represents mean of values cal-
`culated as previously described6 from sequentially measured serum concentrations after ad-
`ministration of a single dose. 0, Fraction absorbed-time profile after food; 0, fraction absorbed
`fasting. Data for Theo-24.‘Z Theo-Dur Sprinkle," and Theo-Dur tablets?” have been published
`previously whereas data for Slo-bid are unpublished (Weinberger et al., 1984). (From Weinberger
`M. Clinical and pharmacokinetic concerns of 24-hour dosing with theophylline. Ann Allergy
`1986;56:2-8.)
`
`23% of intervals when serum concentrations were
`measured twice in the same subjects given the same
`product. Moreover,
`in five of the 10 patients serum
`concentrations increased above 25 ug/ml with one
`product even though they were <20 ug/ml with one
`of the other products. Three of these five had symp-
`toms of theophylline toxicity at the higher serum con-
`centrations but not when given the same dose of a
`different product that resulted in concentrations <20
`ug/ml. Thus, the substitution of one brand for another
`by the pharmacist could result in a change in asthmatic
`control or increased frequency of toxic serum con—
`centrations.
`
`With the current emphasis on generic drug substi-
`tution, physicians may not be aware which formula-
`tion has been dispensed for their patient. Because they
`are not accustomed to attributing changes in clinical
`condition to a formulation change,
`it
`is likely that
`clinical changes will be attributed to other causes and
`result in addition of omer drugs, dosage reduction, or
`discontinuation of theophylline. Because pharmacies
`often change brands of generic products on the basis
`
`of acquisition cost, it is possible for a patient to get
`a different formulation with each refill. At the least.
`any money saved by changing to a less expensive
`generic product will be offset by the cost of measuring
`an additional theophylline serum concentration. usu-
`ally about $40. We therefore recommend that all pre-
`scriptions for slow-release theophylline products be
`written for a specific brand name product and that the
`physician direct the pharmacist not to substitute an-
`other formulation.
`
`FACTORS AFFECTING THE ABSORPTION 0F
`SLOW-RELEASE PRODUCTS
`
`Food. Food affects the absorption characteristics of
`slow-release products in different ways depending on
`the formulation (Fig. 3). In addition, the composition
`of the meal and the timing of the dose with respect
`to the meal may alter the magnitude of the effect.lg
`Food decreases the extent of theophylline absorp-
`tion from Theo-Dur Sprinkle capsules” " but has no
`clinically important effect on Somophyllin-CRT (Fi—
`sons Corp., Bedford, Mass.)'9 Slo-bid (Rorer) (M.
`
`Page 5
`
`Page 5
`
`

`

`the serum concentration lluctuations but had no effect
`on Theo-Dar tablets \x hen git en in a L'rt)sst)\ er design
`stud} to 13 healthy Volunteers." Because dissolution
`of .\'uelin Depot ('I‘heolair-SR. Respbidl
`is pH de-
`pendent. antacids increase the rate of dissolution and
`thus increase the rate of absorption. Presumabl} if a
`
`product
`\sith pHedcpcndenl dissolution ie.g
`2-1. Theolair—SRl
`is goen to an elderl} patient uith
`achlorhydria or concurrentl} mth an H; antagonist
`such as ranitidine. \\hich \muld inhibit hydrochloric
`acid production in the stomach. the rate of absorption
`might increase.
`In contrast. Sbargel et alt" found no
`significant effect of antacids on absorption of Slo-
`Phyllin Gyrocaps or theoph) Iline from plain uncoated
`tablets. \\hich have pH-independent dissolution. Ad-
`ditional studies are required to detinc the effects of
`other factors that might alter the absorption charac-
`teristics of a slo\\»releasc formulation. such as diar-
`rhea. constipalion. and e\tretttes in age.
`'I‘ablet-toaablet.
`lotetovlot. dosedo—dose. and pa-
`tient—to-patient variabilit} in the rate and extent of
`absorption are all factors that' could influence the per—
`formance of slou~release products, Although these
`factors ha\e not been adequatel} evaluated for most
`products. a\aiIabIe data suggest
`that
`there is some
`degree of lot—lodot
`\‘ariabilit_\'.‘ Dose-to-dose \ari~
`abilit} has also been demonstrated in a group of pa-
`tients with a histor) of erratic theophylline levelsf
`and circadian Variation in absorption has been dem-
`onstrated for both rapid- and slim-release products *‘
`In general. boom er. differences bemeen formulations
`are greater than the differences between lots of the
`same product.‘ or between doses in the satne patient,
`
`FDA APPROVAL OF PRODUCTS
`
`Because of a loophole in the Ian. se\eral formu-
`lations of sloH-rclease theoph)lline prodUcts hate
`been marketed without prior apprmal from the Food
`and Drug Administration, Even when approVal has
`been obtained.
`I10\\‘C\ er. FDA eutluation criteria at
`times have been inadequate. Before March 1984. the
`FDA required that bioavatlahilit} studies be conducted
`in healthy nonsmoking men between 25 and 35 years
`of age and in the fasting state, Because the theoplr
`_\lline elimination rate in this population is slots.”
`serum concentration fluctuations are much smaller
`than those seen with the same product in patients with
`more rapid elimination 1 Fig. 5). Thus. products have
`been upprOVCd for t\\ice~a—da_\ administration on the
`basis of small fluctuations in a select population of
`subjects \\ ho are not representatne of the entire pop
`ulation.
`In addition. because manufacturers were re,
`quired to conduct studies only in fasting subjects.
`clinically important effects of food on Theo-24” and
`
`Page 6
`
`\ R
`
`tO
`
`a
`
`_
`E
`B,
`‘5
`
`.-,.
`
`4‘
`
`.2
`E-
`f;
`o
`a:
`i5
`h
`g
`g 2
`
`;\
`,0
`
`i
`.0 ’,
`
`.
`
`l
`‘5?
`l
`
`3
`
`‘.
`‘
`
`5
`\Q
`\
`
`i.
`it
`Q
`Q
`
`\
`
`‘.
`h
`7S
`
`o
`
`o
`
`6
`
`t2
`
`\M'
`t8 2430364248546066 72
`Time, hr
`
`FIG. 4. Mean theophylline serum concentrations in 12
`healthy male nonsmokers after a single 800 mg dose of
`Uniphvl fasting( land after 3 bacon and eggs breakfast
`(ol. Relative to oral liquid reference product, only 53% of
`dose was absorbed during fasting regimen whereas an
`average of 83% was absorbed when dose was taken after
`food. Rate of absorption was only slightly increased dur»
`ing food regimen "' (From Karim A, Burns T, Wearley L,
`Streicher J. Palmer M. Foodeinduced changes in theoph-
`ylline absorption from controlledrelease formulations.
`Part l. Clin PharmacolTher1985;38:77.i
`
`tablets
`Weinbergcr. unpublished data). Theo-Dar
`ilx'eyi." 3: or Theo-bid capsules (Glaxo Inc. Research
`Triangle Park. N. Cr: ITable IIl.
`Itt contrast. food
`increases the extent btit not the rate of absorption of
`Theograd.” a slots-release product available in Eu-
`rope. With 'l‘heoQ-l. food causes an increase in event
`and such a precipitous increase in rate ot absorption
`Ii.e . dose dumpingl that escessixe serum le\e|s and
`clinical to\icit_\' developed in se\eral subjects during
`a Mom ailabilit} stud)‘ t Fig. 31, In sitnilar studies L'n-
`tphyl “as onl} 53‘} to (159 absorbed “hen taken
`fasting \xhereas approximately 83‘} of the dose was
`absorbed after a bacon and eggs breakfast“ :1 (Fig.
`4). The results after multiple doses of L'niphsl at
`steady state “ere nearly identical; 61W ol
`the dose
`\\ as absorbed \\ hen taken fasting cotnpared unit 36‘}
`after food.“
`
`the other factors that could
`Orlier‘jat'lor'i. Fe“ ol
`potentially affect
`the absorption characteristics of a
`slow-release formulation haw been investigated In
`one study M} hre and \‘t'alstad:< demonstrated that con—
`current administration of an antacid \\ ith Nuelin Depot
`lTheolainSR [Riker Laboratories. Northridge. Califl
`and Respbid [Boehringcr
`Ingelheim. Ridgetield.
`Conn] in the L'nited States) resulted in a doubling of
`
`Page 6
`
`

`

`Serum Theophylline
`Concentration (meg/ml)
`' 7.9 noun
`25
`neon Tu,
`Mean Dose ' 3.5 rug/kg 012 hours
`N : 14
`
`20
`
`O’NO Theolnir-SR
`0—. Theo-our 200300
`
`15
`
`1O
`
`
`
`5 O
`
`m, : 1.9 hours
`Dose »’ 3.5 lug/kg 012 hour!
`
`25
`20
`
`15
`
`10
`
`_..-
`.Afim2$2;9&gko~ama
`
`“no-“.0
`.
`
`5 L—l_l_J._l_l_l_l_l_.l_l_l
`
`6
`
`8
`
`1O
`
`12
`
`0
`
`0
`
`2
`
`4
`
`25
`20
`
`' 3.1 hours
`TV,
`10.9 rug/kg 012 hours
`Theollir-SH Dose
`Yheo-dur Dose ' 12.8 mg/kg 012 hours
`
`
`
`”‘0‘.'00.
`
`.
`
`'o.
`
`_ ‘o. . . _
`
`”—n.
`
`o.
`
`'0
`
`0
`
`O
`
`.
`
`2
`
`4
`
`6
`Time (hours)
`
`8
`
`10
`
`12
`
`FIG. 5. Top, Measured mean steady—state serum concentrations among 14 adult volunteers
`receiving Theo-Dur tablets and Theolair-SR at a dose of 250 mg every 12 hours in a crossover
`study conducted by Talseth et al.” Middle, Predicted serum concentrations tor both products
`at same dose and at ti, of 7.9 hours (same as estimated mean 112 calculated for 14 volunteers
`in study by Talseth et al.). Bottom, Predicted concentrations for average child with 1.2 = 3.7
`hours at doses calculated to achieve peak of 15 ug/ml. Mean predicted serum concentrations
`for subjects in study by Talseth et al. (middle) are nearly identical to mean measured levels
`(top). In children, predicted serum concentrations for more rapidly absorbed Theolair-SR are in
`subtherapeutic range for 5 hours of each 12-hour dosing interval. Predicted fluctuations of 53%
`and 16% for Theolair-SR and Theo-Dur, respectively, in average nonsmoking adult increase to
`149% and 38%, respectively, in patient with more rapid elimination. (From Hendeles L, Wein-
`berger M. Theophylline: a "state of the art” review. Pharmacotherapy 1983;322-44.)
`
`Uniphyl,” 2‘ for example, were completely missed
`during the FDA approval process. Consequently. FDA
`approval of a product does not always ensure adequate
`or consistent absorption characteristics, and data used
`
`by manufacturers to support claims for product per-
`formance (e.g., dosing every 12 or every 24 hours)
`can be specious.
`With revisions made in I984,
`
`the FDA now rec-
`
`Page 7
`
`
`
`Page 7
`
`

`

`TABLE II. Summary of effects of food on theophylline absorption from various formulations
`
`
`
` Formulation Extent of absorption Rate of absorption Reference
`
`
`
`
`
`None
`None
`None
`
`Non:
`None
`
`Slightly slower
`Slower
`Slightly slower
`
`Slightly slower
`Slower
`
`Reduced from 91% fasting to
`Jll‘i utter food
`
`Increased from 64-" tasting to
`90” after food
`None
`
`Much slower
`
`Slightly slower
`
`Much slower
`
`‘13
`’
`l9
`
`33
`ill-23
`
`13. H
`
`lo
`
`34
`
`Plain tablets and liquids
`Slo-bid
`SomophyllianRT
`Somophyllin-lZ
`Theobid Duracap
`Theorl)ur tablets
`Pulmi'dur
`Sustaire
`Theoliri Retard
`
`'l‘heo-Dur Sprinkle capsules
`
`Theograd
`
`TheolairSR
`Nuelin Depot
`Nueliii Retard
`Resphitl
`ThcoJ-l
`
`PrecipitoUsly increased
`Increased from 7l’t
`{dose dumping!
`100‘} after food
`[4. 2-1
`Slightly slower
`Increased front ol’r' fasting to
`L‘nipbyl
`83‘2 after food
`
`tasting to
`
`12.
`
`I4
`
`'\\einberger .\I et al,. 193-1. unpublished data; mean data presented in l-ig
`
`omniends that manufacturers include the effects of
`
`food in bioavailability studies of new products. It also
`requires that package inserts of previously approved
`products contain a food warning unless data to the
`contrary have been submitted However. current reg—
`ulatiotis appear not to allow the FDA to require food
`studies on approved products. and thus the perfor-
`mance of such studies is voluntary.
`information
`To provide physicians with sufficient
`to make informed decisions about products and dosing
`intervals we recommend that the FDA require all man-
`ufacturers to disclose quantitatively. iii product llllttfe
`mation brochures and advenisements. the estent and
`
`the degree of lot-
`rate of absorption of the product.
`to-lot variability. the expected percent fluctuation for
`patients with different rates of elimination when given
`every 8. 13. or 24 hours. and the effects of food.
`antactds. and other influencing factors
`
`SELECTING A PRODUCT
`
`The goal for continuoUs therapy with theophylline
`for the management of chronic asthma is to maintain
`relatively constant serum concentrations within the ll)
`to 20 ug ml range around—the-clock. To select a reg—
`imen that will accomplish this goal. the phy sician must
`select a dosing interval appropriate for the absorption
`characteristics of the product and the rate of theoph-
`ylline elimination from the patient. Therapy can be
`
`in «1100‘;
`likely to result
`initiated with a product
`fluctuation with every 12 hour dosing for the patient‘s
`expected rate of elimination (Table I).
`If the patient
`requires larger than average doses or if increased asth—
`matic symptoms occur before a dose. the product can
`be changed to one with a slower absorption rate
`(smaller expected percent fluctuation). or the same
`total daily dose can be divided into Show intervals.
`Either strategy will result in reduced serum concen-
`tration fluctuations.
`
`None of the products currently approved for once—
`aiday administration is capable of achieving the goal
`of maintaining relatively constant serum levels under
`a variety of conditions. Thus. until
`there is a major
`technologic breakthrough in formulation design.
`patients should be receiving theophylline once a day.
`Formulations available as bead-tilled capsules in
`appropriate unit sizes have been administered to chil-
`dren too young to swallow capsules or tablets whole
`by sprinkling the beads on a spoonful of food. At least
`one formulation that
`is completely absorbed in the
`presence of food can be given at 12-hour intervals to
`toddlers with average or lower than average dose re~
`quirements “’ However.
`this product might best be
`administered every 8 hours iii patients who require
`>34 mg‘kg‘day to keep fluctuations <I0(.l‘i. Bead,
`filled capsules with more rapid absorption mUst be
`given every 8 hours to most children. although con-
`
`
`
`Page 8
`
`Page 8
`
`

`

`siderable fluctuation in serum concentration may still
`occur 3‘
`
`REFERENCES
`l.
`
`2.
`
`Waxler SH. Schack .IA. Administration of aminophylline (the-
`ophylline ethylenediamine). JAMA 1950;143:736.
`Hendeles L. Weinberger M. Bighley L. Absolute bioavail-
`ability of oral theophylline. Am J Hosp Pharm 1977;34:525.
`. Jonkrnan JHG. Berg WC. Schoenmaker R. DeZeeuw RA.
`Greving JE, Orie NGM. Disposition and clinical phannaco
`kinetics of microcrystalline theophylline. Eur] Clin Pharmacol
`1980;17:379.
`. Ginchansky E. Weinberger M. Relationship of theophylline
`clearance to oral dosage in children with chronic asthma. J
`Pediatr 1977;91:655.
`. Weinberger M. Hendeles L. Wong L. Vaughan L. Relationship
`of formulation and dosing interval to fluctuation of sentm the«
`ophylline concentration in children with chronic asthma. .1 Fe
`diatr 1981;99:145.
`Weinberger M. Hendeles L. Bighley L. The relation of product
`formulation to absorption of oral theophylline. N Engl J Med
`1978;299:852.
`. Tabachnik E, Scott P. Correia I. et a1. Sustained release the-
`ophylline: a significant advance in the treatment of childhood
`asthma. J Pediatr 1982;100:489.
`Hendeles L, lafrate P. Weinberger M. A clinical and phar»
`macokinetic basis for the selection and use of slow release
`theophylline products. Clin Phannacokinet 1984:9295.
`. Spangler DL. Kalof DD. Bloom FL. Wittig HI. Theophylline
`bioavailability following oral administration of six sustained-
`release preparations. Ann Allergy l978:40:6.
`Spangler DL, Vanderpool GE, Carroll MS. Tinkelman DG.
`Bioavailability and multiple dose characteristics of a new sus-
`tained release theophylline tablet. Ann Allergy 1980;45:355.
`Weinberger MM. Theophylline qid, tid, bid and now qd? A
`report on 24-hour dosing with slow-release theophylline for-
`mulations with emphasis on analyses of data used to obtain
`Food and Drug Administration approval for Theo—24. Phar-
`macotherapy l984;4:181.
`Hendeles L. Weinberger M. Milavetz G. Hill M. Vaughan L.
`Food-induced dose dumping from a "once-a»day' ‘ theophylline
`product as a cause of theophylline toxicity. Chest 1985;87:758.
`Pedersen S. Moller-Pederson I. Erratic absorption of a slow
`release theophylline sprinkle product caused by food. Pediat»
`rics 1984;74:534.
`Karim A. Burns T. Wearley L. Streicher J, Palmer M. Food-
`induced changes in theophylline absorption from controlled-
`release formulations. Part
`I. Substantial
`increased and de-
`creased absorption with Uniphyl tablets and Theo-Dur Sprin-
`kle. Clin Pharmacol Ther [985;38177.
`Fagerstrom P0. Heintz L. Absorption of sustained-release the-
`ophylline tablets. Int .1 Clin Pharmacol Ther Toxicol 1983:
`21:359.
`Lagas M. Jonkman JHG. Greatly enhanced bioavailability of
`theophylline on postprandial administration of a sustained re-
`lease tablet. Eur J Clin Pharmacol 1983;24:761.
`Baker IR. Moessner H. Gonzaliz U. et a1. Variability in the-
`ophyllin