Theophylline product and dosing interval selection for chronic asthma

Leslie Hendeles, Pharm.D.,* and Miles Weinberger, M.D.** Gainesville, Fla., and Iowu City, Iowa

Unless they are taken at unacceptably ,frequent intervals, conventional rapid-release theophyllintj tablets and liquids produce excessive Serum concentration jluctuations, particularly in patients with rapid elimination. Slow-release ,formulations provide more stable serum concentrations with longer dosing intervals if absorbed completely, consistently, and ut a suficiently slow rate and thus have the potential to improve @cacx and compliance. However, there are clinical!\ important d$ferences in the extent and rate qf absorption among the IS slow-release,formulation.s available under 29 brand names in the United States. Fluctuations in steady-state serum concentrutions are a function qf the absorption rate qf the product, the eliminution rate of the patient, and the dosing interval. In patients with slow elimination, cliniculiy relevant diffurences crmong ,formulations are not apparent with twlice-dail! dosing. Among patients with more rapid elimination, how,ever. available data fbr only t+tlo products demon.strate suficiently .slo~, clbsorption to justify routine t\r,ice-daily use without e.rces.sive ,fluctuations. More rapidI> ab.sorbed ,f(~rmulation.s must be administered at X-hour intervals in such patients to prevrnt breakthrough in asthmatic symptoms b<fore the next dose, despite promotional c1aim.s to the contrary. Current products approved .for- ’ ‘once-a-day’ ’ dosing are clinically inadequate because of incomplete or erratic absorption or excessive serum concentrution ,fluctuation.s. La.stly. [ood intake induces dose dumping of potentially toxic amounts of’ theophylline Jrom Theo- 24 and great!\‘ impairs absorption ,from Theo-Dur Sprinkle capsules but has no important effect on Theo-Dur tablets. The eflects of,fbod on most other theophylline products are not known. (J ALLERGY CLIN IMM[JWL 76:2&Y-91, 1985.)

In the late 196Os, advances in pharmaceutic tech- nology resulted in the availability of slow-release for- mulations for several drugs. In most cases, these dos- age forms were promoted to decrease the number of daily doses required to provide greater convenience for the patient and to improve compliance. In contrast, slow-release theophylline products were developed primarily out of therapeutic necessity. Conventional liquid formulations and plain uncoated tablets that undergo rapid dissolution frequently produce exces- sive serum concentration fluctuations, particularly in patients with rapid elimination, even when intervals between doses are as short as 6 hours.‘.’ Formulations that decrease the rate of absorption potentially result in more stable serum concentrations, and a recent crossover study of 35 children with chronic asthma suggested greater efficacy and improved compliance

From the rDivision of Clinical Pharmacokinetics, College of Phar- macy and Department of Pediatrics, University of Florida. Gainesville, Fla.; and the *“Pediatric Allergy and Pulmonary

Division. The University of Iowa. Iowa City. Iowa. Reprint quests: Leslie Hcndeles, Pharm.D.. University of Florida

IBOX J-4). Gainewillc. FL 32610.

Abbreviations used FDA: Food and Drug Administration AUC: Area under the serum concentration-time

curve t’/?: Elimination half-life

when doses of a slow-release theophylline product were given every 12 hours, than when the same total daily dosage of plain tablets was given every 6 hours.’ Thus slow-release products-if absorbed completely, consistently, and at a sufficiently slow rate-have the potential to provide convenient around-the-clock sta- bilization of the hyperreactive airways characteristic of chronic asthma. Achievement of this goal, however, depends on the degree of airway reactivity in an in- dividual and the amount of fluctuation in serum con- centrations. Because fluctuations are a function of the rate of absorption of the product, the rate of drug elimination from the patient, and the length of the dosing interval,” the product and dosing interval must be selected to provide acceptable fluctuations for the degree of airway reactivity in the individual patient.

285

286 Hendeles and Weinberger J ALLERGY CLIN. IMMUNOL. AUGUST i985

Fractlor Absorbed

-LI1ll I i 11111 I / 111 I I 111

o 2 4 6 8 10 12 14 16 18 20 22 24

Time (hours)

FIG. 1. Rate and completeness of absorption of four slow- release theophylline formulations and plain uncoated tab- lets. Each determination of the cumulative fraction ab- sorbed represents the mean of values calculated from sequentially measured serum concentrations after single doses of the slow-release product and a rapidly absorbed reference product to adult subjects.5 (Reproduced with permission from Hendeles and Weinberger.?

In patients with very mild asthma, acceptable control of symptoms may be achieved even when serum con- centration fluctuations are large. In such patients, maintenance therapy with theophylline may not even be necessary. However, as the severity of the disease increases, the likelihood of benefit from theophylline increases when serum concentrations remain relatively constant within the 10 to 20 p&/ml therapeutic range around-the-clock.’

EVALUATION OF PRODUCTS

At last count, 15 brands of slow-release theoph- ylline formulations were available under 29 brand names in the United States (see Table I). These prod- ucts are formulated in various ways to decrease the rate of disintegration and dissolution of the drug. However, differences in formulation design have re- sulted in clinically important differences in complete- ness. rate, and consistency of absorption.‘- ‘~’ More- over. because of a loophole in the law, over half these products have been marketed without prior approval from the FDA, and even when approval has been ob- tained, FDA evaluation criteria have often been in- adequate. Before March 1984, the FDA required that bioavailability studies be conducted in healthy male subjects between 25 and 35 years of age in the fasting state. Because the theophylline elimination rate in this population is slow,’ serum concentration fluctuations are much smaller than those seen with the same prod- uct in patients with more rapid elimination.‘,” In ad- dition, because manufacturers were required to con- duct studies in fasting subjects, clinically important effects of food have been completely missed during the FDA approval process. Consequently, FDA ap- proval has had limited meaning and data used by man-

ufacturers to support claims for product performance (e.g., dosing every 12 or every 24 hours) must be critically evaluated.

Extent of absorption

The amount of drug absorbed into systemic circu-

lation is directly proportional to the AUC. The AUC is measured by dividing the serum concentration-time curve into trapezoids, calculating the area of each trapezoid, and summing the results. The extent of absorption can be calculated from the ratio of the AUC of a slow-release product and that of a 100% absorbed

reference product, such as an intravenous or oral so- lution or a plain uncoated tablet, after single or mul- tiple doses given to the same subjects in a crossover design.4 In this manner, complete absorption has been demonstrated for most slow-release products. How- ever, Tedral-SA,’ Labid,” Theo-24 (fasting),“‘.” Theo- dur Sprinkle capsules (with food),” Ii Uniphyl (fast- ing),” and two products available outside the United States, Euphyllin RetardI and Theograd (fasting),15 were incompletely absorbed. Earlier studies’ sug- gested that absorption of theophylline from Aerolate, Aminodur, and Theobid may have been incomplete, but these products have been reformulated and cur- rently appear to be completely absorbed. Because of inadequate study design, the extent of absorption of Constant-T was indeterminable,’ and data could not be obtained from the manufacturers of Duraphyl (Theochron) and Provent (a “ 12-hour” product avail- able outside the United States with a formulation de- sign very similar to Theo-24).

Incomplete absorption may have important clinical consequences. If the dose of an incompletely absorbed product is increased to achieve a serum concentration within the 10 to 20 p&/ml optimal range and if the product is subsequently given under conditions in which absorption becomes complete. or if the patient is subsequently changed to the same dose of a com- pletely absorbed oral product or an intravenous reg- imen during an acute exacerbation, serum concentra- tions will increase, possibly to toxic concentrations. Because the serum concentration often increases dis- proportionately to the increase in amount of drug ab- sorbed as a result of dose-dependent kinetics, the like- lihood of producing toxic concentrations is particu- larly great. Conversely, if the dose is initially adjusted to achieve serum concentrations in the IO to 20 kg/ ml range with a 100% absorbed product and the patient is subsequently changed to an incompletely absorbed product, serum concentrations will decrease to sub- therapeutic concentrations, which might result in ex- acerbation of asthmatic symptoms. These problems are even more likely if the dispensing pharmacist makes a “generic substitution” without consulting the

VOLUME 76 NIJMBER 2. PAHT 2

Theophylline product and dosing interval 287

TABLE I. Extent of absorption and predicted fluctuations in serum concentrations during a 12-hour dose interval of various slow-release theophylline products*

Manufacturer Brand name Extent of absorption

(%I

% Fluctuationt

V/z = 3.7 hr t% = 7.7 hr

Plain tablets Rorer. Johnson & Johnson.

Riker Bead-tilled capsules

Central Pharmacal

Cord Laboratories

Graham Laboratories

Key Pharmaceuticals K-l’ Laboratories

Rorer Searle

Slow-release tablets Cord Laboratories Key Pharmaceuticals

Mead Johnson Mundipharma Norwich Eaton

Parke-Davis Purdue Frederick Riker

Slo-Phyllin, Theophyl,i TheolairZ

100 465 125

Physpan, Quibron-BID. Theoclear LA, 3 Theon-300, Theo-

span-SR Bronkodyl S-R, Slo-

Phyllin Gyr0caps.i: Theophyl-SR

Aerolate, Somophyllin- CRT$

Theo-Dur Sprinkle Elixophyllin SR, Theobid Theovent-LA Slo-bid Theo-24$

Constant-T 76 Theo-Dur$ 200, 300 97 Theo-Dur$ 100 103 Quibron TISRS 99 Phyllocontin 95 LaBID$ 87 Choledyl SA 93 UniphylS# 551809 Theolair-SR, Resbid 99

95 240 73

99

101

911445 94 94

101 71/100~

230

130

II II 140 54 167 60 43 IX

155 57 39 17 88 35

128 4x 165 SX 252 77 154 57

73

47

/I 1’

*Adapted from Hendeles L, Iafrate P, Weinberger M: A clinical and pharmacokinetic basis for the selection and use of slow release theophylline products. Clin Pharmacokinet 9:95, 1984.

i-Percent fluctuation = [(Peak - trough serum concentration)itrough serum concentration] x 100; actual fuctuations may somewhat exceed predictions because of circadian variation in absorption.” The t% values are the median value for the average child (3.7 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 >lOOR 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 )~g/ml are attained; X-hour intervals are then advisable, regardless of advertising claims for twice-daily or l2-hour dosing. Methodology and validation of the derivation of these values have been described.”

$FDA approved as of September 1984. Because the approval process has not adequately considered the pharmacokinetics and pharmd-

codynamics of theophylline. “approval” is not an appropriate basis for selecting or rejecting formulations or choosing adequate dosing intervals.

SExtent of absorption when taken fasting and with food, respectively. l(Becauae rate and completeness of absorption change with food. meaningful predictions of fluctuations cannot be made. *lpH-Dependent dissolution may alter the rate of absorption depending on gastric pH and emptying.‘* Therefore. meaningful predictions

of fluctuations can not be made. #Unlike the other products listed in this table, data for Uniphyl have not been directly examined and analyzed by the authors. Conclusions

are based on a presentation at a national scientific meeting.”

prescribing physician. In addition, products that are incompletely absorbed may also be more inconsis- tently absorbed, a problem documented with the old Aerolate formulation.‘6 For these reasons, it is best to avoid products with incomplete absorption whenever possible.

Rate of absorption

When serum concentrations are measured over a sufficient length of time after administration of a single dose of a slow-release product, the rate of absorption can be determined from the cumulative fraction of the dose absorbed over time’ (Fig. 1). When the various

288 Wendeles and Weinberger J ALLERGY CLIN, I~~U~OL. AUGUSl :985

Sertim Th~ophyiline o.wW

steady-state serum concentrations can bc calculated:

30 # PI&, Tsbhrls. 6 Zm&‘kg 91% oic Fluctuation = ([Peak -- trou~h]/t~~)ugh~ X 100. Cl Theo-Dur 200 6.300 12 8mg/kp q12h

25 l PhyllOwnlin. 12 3mp/kp qlZh Because the width of the therapeutic range is only IO 0 Slophyllin Gyrocaps, IOmg/kp 912n , Tha*illir SR 1CemQi’kQ q*m

pgiml, fluctuations must be <loo% to maintain SC- 20 rum concentrations within the therapeutic range, even

15 when the peak is as high as 20 tJ.giml. When slow- release products are compared in this manner. aft con-

10 pletely absorbed products will be associated with I-& 5 atively small fluctuations in serum ~on~cntration~ it

0 administered <every 12 hours to the average nonsmok-

0 12 3 4 5 6 7 8 91011?2 ing adult’.’ in whom the median t% is about X hours Time (hours) (Table If. fn fact, in these patients ~~~l~~nati~~n is siow

FIG. 2. Predicted steady-state serum concentrations for an average child (V/z = 3.7 hours, volume of distribution =- 0.5 L/kg) receiving plain uncoated tablets and the four slow-refease products in Fig. 1 at 12-hour dosing intervals, Doses were calculated to achieve a 15 pgiml peak serum concentration. The more rapid the rate of ~bsorption~ the greater the ffuctuations and the longer the serum con- centration remains subtherapeutic (<IO ~gimi). Predicted fluctuations in serum concentrations for the plain tablets, Slo-Phyliin Gyrocaps, Phyllocontin, Theoiair-SR, and Theo-Dur 300 mg tablets are 459% 225%, 165%, I@%,

and 38%, respectively. Predicted serum concentrations of Sto-bid Gyrocaps (not shown) are similar to Theo-Our tab- lets with a 43% predicted fluctuation. These predictions slightly underestimate actual fluctuations, because the method does not reflect the circadian variation in absorp- tion observed for both rapid- and slow-release formula- tions.” Adjusting the dose rather than the dosing interval will not alter the percentage fluctuation. Therefore, chil- dren, smoking adults, and about 25% of otherwise healthy nonsmoking adults will generally require X-hour dosing intervals for most slow-release products, that is, those with predicted fluctuations greater than 100% at a t% of 3.7 hours. (Hendeles L, Weinberger M: Improved efficacy and safety of theophylline for control of airways hyper- reactivity. Ann Altergy 49:247, 1982.~

slow-release products are compared in this manner, marked differences in rates of absorption become readily apparent.‘. ’ ~lo-Phyllin Gyrocaps, for ex- amptc. is one of the more rapid@ absorbed slow- release formulations, while Theo-24 (taken fasting) is so slowly absorbed that its absorption is incomplete. The clinical relevance of differences in the rate of absorption after multiple doses at steady state depends on the rate of el~nlinat~on of the drug from the patient and the dosing interval selected.’

DOSING INTERVAL SELECTION

enough, on average- that serum ~~~ri~entr~~ti~~n fluc- tuations generally will be < 100% with a rapid-release product administered every 8 hours.” However. clin- ically ~mpo~ant differences in abso~t~~n rates be- tween slow-release the~~phylline products become ap- parent when steady-state serum ~~~n~entrati~~ns are predicted for 12-hour dosing intervals in patients who metabolize the drug as rapidly as the average child or cigarette smoking adult f Fig. 2). In these patients, excessive fluctuations can be reduced by selecting a slow-release product with slow enough abs~~~t~~~~~ or by administering the same total daily dose divrded into &hour irtervals.’

Given the interrelationship among rate of ab~np- tion, rate of elimination, and serum concentration fuc- tuations, it is predictable that extending the dosing interval to once-a-day dosing will result in excc\sive fluctuations unless the rate ofabsorpFion of the product or the rate of elimination in the patient is sufficiently slow. Although Theo-24, Theo-Dur tablets, and Uni- phyl have been approved by the FDA for once-a-day ad~ninistrat~on. none of these products achieve\ ref- atively constant serum levels over 24-hour ciosinp in-

tervals under both fastmg and postprandial conditions in most patients. Serum concentration fluctuations

with Theo-Dur tablets, for example. averaged 196%: with dosing every 24 hours compared with 45% with dosing every 12 hours in subjects with a mean 1~~6 of 7 hours.“’ A t!+ of 2 IO hours is reyun-ed for acccpt- able fluctuations with once-daily dosing with this product, but only about 20% of adult nonsmokers eliminate the drug this slowly.‘” Uniphyllin. thu Eu- ropean version of Unlphyl, a product reported to be only 55% absorbed in one study when taken fascmg,” was associated with excessive ~uctuations when given once daily to n~}nsnl~kin~ subjects after breakfast (Fig. 3). In contrast, Theo-24 is absorbed slowly enough when taken fasting to achieve acceptable i-t&- tuations with once-a-day dosing in subjects with a tV5 -35 hours. However, only 7 1% to 78% of the dose is absorbed under fasting conditions.“’ ” thereby rcquir- ing higher doses. and food causes dumping of poten-

Once the rate of absorption of the product is known, stead>,-state serum concentrations after multiple doses can be predicted with reasonable accuracy’ for dif- ferenr dosing intervals in patients with different rates of elimination.’ From these data, fluctuations in

VOLUMl 76 XUMBEN 2. PART 2

Theophylline product and dosing interval 289

Serum Theophylline 20

i

Level (pg/n1-1)

oJ, 0 2 4 6 8 IO 12 14 16 18 20 22 24 hours

*

Sampling lime

FIG. 3. Steady-state theophylline serum concentrations (mean ? SD) in 12 healthy subjects who received, in a randomized, crossover study, Theo-Dur, 300 mg every 12 hours and Uniphyllin, the European version of Uniphyl, 600 mg every 24 hours for 4 days. The morning dose each day was taken after breakfast.” (Reproduced with permission from Purkiss et al.*‘)

tially toxic amounts of theophylline (Fig. 4). There- fore, once-a-day dosing of theophylline appears to be more a marketing ploy than a breakthrough in tech- nology. In fact, two of the pharmaceutical companies whose “once-daily” products could not reliably main- tain serum concentrations within the 10 to 20 kg/ml range with once-a-day dosing unsuccessfully at- tempted to convince the FDA to extend the therapeutic range to 5 to 20 pgiml. In point of fact, results of clinical studies examining the relationship between serum concentration and symptom control” (rather than just pulmonary function), along with consider- able clinical experience by many clinicians over the past decade. unequivocally confirm that IO to 20 pg/ ml is the concentration range most likely to achieve maximum clinical benefit safely.

Formulations available as bead-filled capsules in appropriate unit sizes such as Somophyllin CRT, Slo- Phyllin Gyrocaps, Slo-bid Gyrocaps, and Theo-Dur Sprinkle capsules have been administered to children too young to swallow whole capsules or tablets by sprinkling the beads on a spoonful of food. However, none of these products can be administered every 12 hours in most of these children. Theo-Dur Sprinkle is absorbed slow enough to allow dosing every 12 hours in patients with rapid elimination, but food ingestion reduces the absorption of this product by 60%. ” On the other hand, Slo-bid, which is completely absorbed in the presence of food. suggests that dosing every 12

hours among toddlers with average or higher dose requirements will result in excessive fluctuations. This product, therefore, might best be administered every 8 hours in patients who require >24 mglkgiday to keep fluctuations < lOO%.* Somophyllin CRT and particularly Slo-Phyllin Gyrocaps must be given every 8 hours to most children,‘. 4 but serum concentration fluctuations will be larger with these products than with the more slowly absorbed Slo-bid Gyrocaps given over the same interval. In addition, a minority of patients with extremely rapid metabolism will re- quire dosing every 6 hours with Somophyllin CRT or Slo-Phyllin Gyrocaps to prevent breakthrough in asth- matic symptoms associated with low trough levels before the next dose. In these patients, a more slowly absorbed product administered every 8 hours is re- quired to achieve acceptable fluctuations.

FACTORS AFFECTING RATE AND EXTENT OF ABSORPTION Food ingestion

Food affects the absorption characteristics of slow- release products in different ways depending on the formulation. However, the composition of the food and the timing of the dose with respect to a meal are variables that have not been fully investigated.

Food decreases the extent of theophylline absorp-

“Hendeles et al.: Unpublished obsrvations.

290 Hendeles and Weinberger J. ALLERGY CLIN. IMMUNOL. AUGUST 1985

-0 4 8 12 16 20 24 28 32 36 40 44 48

Time (hrs)

FIG. 4. The cumulative fraction of the dose absorbed (mean 2 SE&l) over time after a single dose of three slow- release products taken fasting (solid symbols) and after food (open symbolsl. Each product was studied with and without food in a crossover design, but data for each prod- uct are from three separate studies.“,13~22 The validity of presenting data from different studies in this manner has been previously documented~ Theo-dur Sprinkle cap- sules ftopl was completely absorbed when taken fasting, but food decreased the rate and markedly reduced the completeness of absorption to only 40% of the dose.‘3 In contrast, Theo-24 (top) was slowly and incompletely ab- sorbed when taken fasting, but food increased the rate of absorption so precipitously (dose dumping) that about 50% of the dose was absorbed over a 4-hour period. After food, Theo-24 was completely absorbed by 24 hours.” Food had no significant effect on the rate or the extent of absorption of Theo-Dur tablets ~bo~om~.z2

tion from Theo-Dur Sprinkle capsules” but has no clinically important effect on Somophyllin CRT, Slo- Bid, Theo-Dur tablets1’.‘“‘4 {Fig. II), or Theobid cap- sules.” In contrast, food increases the extent but de- creases the rate of absorption from Theograd,” a slow- release product available in Europe. With Theo-24 (Puln~o-Tinlelets in some countries), food causes an increase in extent and such a precipitous increase in rate of absorption (i.e., dose dumping) that several sub.jects in a bioavailability study developed excessive serum levels and clinical toxicity. ‘I In a similar study, Uniphyl was only 55% absorbed when taken fasting but was more completely absorbed when taken with food. I2

in vitro dissolution of Theoiair SR depends on PI-I. Food decreases gastric emptying time and slows the rate of absorption, because the product dissolves more

rapidly in the alkaline milieu of the small intestine.‘” Antacids increase the rate of abso~tion from this product”’ but have no effect on the rate or extent of theophylline absorption from products with pH-in- dependent dissolution such as Theo-Dur tablets” or Slo-Phyllin Gyrocaps.“’

For the remaining slow-release products on the United States market. there are no data available on the effects of food because of the previous requirement of the FDA to perform bioavailability studies in the fasting state. These products, if taken at all, should be administered fasting until data become available. As a result of the previously mentioned Theo-24 study. the FDA has recommended that manufacturers of slow-release theophylline products conduct postpran- dial studies. While the current law does not permit the FDA to require that these studies be conducted for approved products, the agency does require a new warning in package inserts stating that food may affect theophylline serum concentrations unless data to the contrary have been submitted.

Other factors

Tablet-to-tablet, lot-to-lot, dose-to-dose, and pa- tient-to-patient variability in the rate and extent of absorption are all factors that characterize perfor- mance of slow-release products. Although these fac- tors have not been adequately evaluated for most slow- release products, what data are available suggest that there is some degree of variability in these four fac- tors. In particular, circadian variation in absorption has been demonstrated with several products including rapid-release formulations; theophylline abso~t~on in the evening is delayed, resulting in lower serum levels after the evening dose compared with levels after the momin~ dose when the drug is administered every 12 hours. I7 lntrapatient variability in serum concentra- tions over a 48-hour period has also been demonstrated in a select population of patient: and probably reflects variation in gastrointestinal function,“’ but this is prob- ably not a clinically important problem for most pa- tients who take slow-release theophylline products. Lastly, lot-to-lot variability in absorption has been demonstrated for several products, but differences be- tween products generally are greater than the differ- ences between lots of the same product.” Because current FDA regulations do not require studies to de- termine lot-to-Iot variability in absorption, the degree of variation among most of the products in the United States is currently unknown.

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VOLUME 76 UUMBFR 2. PART 2

Theophylline product and dosing interval 291

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