Effects of food on the bioavailability of theophylline from controlled-release products in adults

Effects of food on the bioavailability theophylline from controlled-release in adults

of products

Aziz Karim, Ph.D. Skokie, 111. A variety of formulation-dependent food-induced absorption changes (I ‘food effect”) occur with controlled-release formulations crf theophylline. These changes are,found in formulations with either pH-dependent or pH-independent in vitro dissolution characteristics. They include decreases in the rate or extent, increases in the rate and e.rtent, and more erratic or variable theophylline absorption. In evaluating food effects from a test formulation, it is essential to standardize the meal composition (fat content) and dosing time relative to meal intake. For those formulations that exhibit pronounced food effect, drug dosmg relative to meal intake should be made part of product labeling to assure consistent absorption. (J ALLERGYCLIN IMMUNOL 1986;78:69.5-703.)

Food-induced absorption changes (“food effect”) from controlled-release formulations of theophylline have been noted by several investigators.‘-’ Relative to values in the fasting state Vaughan et al4 found increased rate and extent of theophylline absorption from an ultraslow-absorbing formulation, Theo-24 (G. D. Searle &Co., Chicago, Ill.), when this product was given immediately after a high fat content meal. Theo-24 exhibits a pH-dependent theophylline in vitro dissolution rate between pH 1 and 8. In-depth and systematic investigation?’ have been carried out in our laboratories to assess: (1) whether the food effect is unique to formulations with pH-dependent in vitro dissolution profiles or whether it also occurs with formulations without this characteristic; (2) whether the food effect can be minimized by altering the meal composition (fat content), the dosing time relative to meal intake, or both; (3) the combined effect of posture and food on theophylline absorption with the nighttime dosing of a controlled-release product; and (4) the clinical implications of food effect.

FORMULATIONS, SUBJECT CHARACTERISTICS, STUDY DESIGN, AND ANALYTIC TECHNIQUES Four currently marketed controlled-release theophylline formulations with different release mechanisms were selected for detailed investigation of food effect.

Reprint requests:Aziz Karim, Ph.D., Director, Clinical Bioavailability and Pharmacokinetics,G. D. Searle & Co., R & D Division, 4901 Searle Parkway, Skokie, IL 60077.

Abbreviations used C,,,: Maximum serum concentration t,,: Time to maximum serum concentration AUC: Area under the curve C,,.: Minimum serum concentration

These formulations were Theo-24 capsules: pellet capsule formulation with pH-dependent in vitro dissolution; Theo-Dur tablets (Key Pharmaceuticals, Miami, Fls..): pellet compressed tablet formulation with pH-independent in vitro dissolution; Uniphyl tablets (Purdue Frederick, Norwalk, Conn.): cellulose matrix tablet fcrmulation with pH-independent in vitro dissolution; and Theo-Dur Sprinkle (Key): pellet sprinkle formulation with pH-independent in vitro dissolution. Clinical studies were randomized, balanced, crossover, single-dose studies in healthy, young adult, male nonsmokers. Subjects were judged healthy on the basis of history, physical examination results, routine laboratory data, standard ECG, and blood pressure; all subjects weighed within + 10% of the ideal body weight for age and height. Study protocols were approved by Institutional Review Boards, and each subject gave written informed consent. Alcohol- and xanthine-containing foods or beverages were prohibited for 48 hours before, during, and for 72 hours after each drug dosing. No medication was taken by the subjects from 1 week before each study until its completion. The standardized breakfasts contained high or medium fat content. The high-fat breakfast consisted of 695

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Time. hours FIG. 1. Mean serum concentration-time curves of theophylline in 20 healthy, male nonsmokers receiving single doses of aminophylline immediate-release (/R/tablets and Theo-24 capsules or Theo-Dur tablets under fasting conditions and with a high-fat breakfast. Actual dose of aminophylline tablets was 600 mg (480 mg theophylline); however, data are normalized for 900 mg theophylline dose used for Theo-24 and Theo-Dur. (From Karim A. Am Pharm 1985;NS25:132.)

two slices of toasted white bread spread with butter, two eggs fried in butter, two slices of bacon, 56 gm hash brown potatoes, and 0.24 L whole milk (approximately 33 gm protein, 58 to 75 gm fat, 58 gm carbohydrate; 870 to 1020 calories). The medium-fat breakfast consisted of one slice of toasted white bread spread with butter and jelly, 28 gm dry cereal (corn flakes), 0.24 L skim milk, 0.18 L orange juice, and one banana (approximately 17 gm protein, 8 gm fat, 103 gm carbohydrate; 583 calories). In fasting conditions, subjects fasted overnight for at least 10 hours, fasted for an additional 4 hours after drug dosing, and then received the standardized highfat breakfast. All doses were taken with 120 ml water. Dosing was done with the subjects under observation at the clinical facility, and standardized diet and activity were observed during the subjects’ confinement. Blood samples were drawn in Monovette tubes (Walter Sarstedt, Inc., Princeton, N.J.) (or heparinized Vacutainer tubes [Becton-Dickinson, Rutherford, N.J.]) at 0 hours (immediately before dosing) and 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 28, 32, 36, 40, 48, 52, 56, 60, and 72 hours after dosing. Serum theophylline concentrations were determined by an enzyme immunoassay system (EMIT; Syva Co., Palo Alto, Calif.). Between-day coefficients of variation ranged from 3% to 14% at serum concentrations of 0.6 to 20 pg/ml. Concentrations ~0.6 pg/ml (detection limit) were considered as zero in all calculations.

Pharmacokinetic model-independent parameters including C,,,, t,,,, and the AUC (linear trapezoid method) were determined by a standard method. Statistical comparisons of these parameters were made by univariate repeated-measures ANOVA.

DIFFERENT EXAMPLES OF FOOD-INDUCED ABSORPTION CHANGES The four formulations investigated exhibited a variety of food effects, which could be classified as follows. Increase in the rate of absorption, extent of absorption, or both. Figs. 1 and 2 summarize results of a study in which 20 subjects received a single 600 mg dose of immediate-release aminophylline tablets (480 mg theophylline) and a single 900 mg dose of Theo24 (three 300 mg capsules) or Theo-Dur (three 300 mg tablets) administered with the subjects in the fasting state and immediately after a high-fat breakfast.’ In the fasting state, absorption of theophylline from Theo-24 occurred more slowly than absorption from Theo-Dur (Fig. 1). However, when Theo-24 was administered immediately after a high-fat meal, an increase was seen in the rate and extent of theophylline absorption, but the resultant peak serum levels, adjusted for a 900 mg dose, were almost half those attained with an immediate-release product and similar to those attained with Theo-Dur tablets given under fasting conditions or with a high-fat meal (Figs.

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FIG. 2. Individual points and mean (*SD) maximum serum concentrations of theophylline in 20 healthy, male nonsmokers receiving single 900 mg doses of Theo-24 and Theo-Dur under fasting conditions and immediately after a high-fat breakfa:st. N.S., Not significant. (From Karim A. Am Pharm 1985;NS25:132.)

1 and 2). With a high-fat meal the absorption profile of Theo-24 was therefore altered from a product exhibiting ultraslow absorption to a product having a lag period followed by an absorption profile somewhat similar to that of Theo-Dur. Use of the expression “dose dumping,” which has been widely attributed to food-induced absorption changes with Theo-24, is therefore inappropriate.5 The effect of’a high-fat breakfast on theophylline absorption from Uniphyl was assessed in another study.6 Figs. 3 and 4 present data in 12 subjects who received a single 800 mg dose of Uniphyl (two 400 mg tablets) while in the fasting state and immediately after a high-fat breakfast. These subjects also received a single 600 mg dose of immediate-release aminophylline tablets (480 mg theophylline) in the fasting state. The C,, of theophylline (mean t SD) after immediate-release aminophylline tablets was 12.5 + 2.2 pg/ml. With reference to the fully bioavailable immediate-release product, a marked enhancement of theophylline absorption occurred from 53 ? 23% (mean 2 SD) to 96 + 46% when Uniphyl was dosed in fasting and nonfasting states, respectively.6 There was also approximately 100% increase in C,,, (from 4.5 to 8.6 pg/ml) and AUC (0 to 72) values (from 99.60 to 179.15 pg/hr/ml). Lagas and Jonkman’ also found a food-induced (high fat) absorption increase with Theograd tablets (Abbott Laboratories, North Chicago, Ill.) (Fig. 5)) a porous matrix controlled-release formulation that

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FIG. 3. Mean (-c SD) serum theophylline concentrationtime curves in 12 subjects after single 800 mg doses of Uniphyl (two 400 mg tablets) given under fasting conditions (0) and immediately after a high-fat breakfast (~1.

exhibits pH-independent in vitro dissolution characteristics. The extent of theophylline absorption relative to a fully bioavailable reference aminophylline solution increased from 64 ? 22% (mean * SD; n = 6) to 90 + 13% when Theograd tablets were given while subjects were fasting and nonfasting, respectively.

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FIG. 4. Individual points and mean (*SD) values of theophylline C,,, and AUC (0 to 72) in 12 subjects after single 800 mg doses of Uniphyl tablets given under fasting conditions and immediately after a high-fat breakfast.

Pedersen’ found food effect with Neulin Retard (Theolair Retard, Riker Laboratories, Northridge, Calif.). The rate of absorption of theophylline from this product was significantly faster (average f,, = 3.6 hours) in a fasting state than in a nonfasting state (average t,,, = 9.2 hours). Also, the mean AUC (0 to 12) in a nonfasting state was only 60% of the AUC (0 to 12) in a fasting state. Decrease in the extent of absorption. An example of a pronounced food-induced decrease in the extent of theophylline absorption is illustrated in Figs. 6 and 7. In this study, six subjects received 900 mg TheoDur Sprinkle (over applesauce) under fasting conditions and immediately after a high-fat breakfast. The food-induced decreases in C,,, and AUC averaged 59% and 47%, respectively, whereas the fax remained essentially unchanged.6 These findings were similar to those of Pedersen and Moller-Petersen.’

FORMULATION FACTORS The above studies demonstrate a variety of foodinduced absorption changes when controlled-release formulations of theophylline are administered with food that contains a high fat content. Even though both Theo-24 and Theo-Dur Sprinkle are beaded products, the food effect with Theo-24 resulted in an increase in the rate and extent, whereas with Theo-Dur Sprinkle a decrease in the extent of theophylline absorption was observed. Food-induced absorption changes are not unique to formulations that exhibit pH-dependent in vitro dissolution characteristics. With Theo-Dur Sprinkle,

Uniphyl tablets, and Theograd tablets, theophylline in vitro dissolution rate is not altered at pHs between 1 and 8, and yet all three products exhibit a food effect. With Theo-Dur Sprinkle a decrease was seen, whereas with Uniphyl and Theograd tablets an increase in the extent of theophylline absorption was found. Ingestion of a large, high-fat meal is known to delay gastric emptying and increase secretion of bile, pancreatic fluid, enzymes, and hormones. A combination of one or more of these physiologic factors may contribute to changes in the release or absorption of theophylline from controlled-release formulations. An in vivo study is therefore essential to assessthe food effect from a test controlled-release formulation. Recently a variety of in vitro systems that predict food effect have been investigated, and the initial findings appear Iencouraging.8, 9 Introduction of such in vitro systems would assist in screening out formulations that may show a pronounced food effect in vivo.

IMPORTANCE OF MEAL COMPOSITION AND DOSING TIME RELATIVE TO MEAL INTAKE IN ASSESSING CHANGES IN ABSORPTION Because a marked food-induced increase in the rate and extent of theophylline absorption was found with Theo-24., it was of interest to assess whether these changes can be minimized by altering the meal composition, dosing time, or both relative to meal intake.7 Both these factors were found to be important in reducing the food effect. Figs. 8 and 9 illustrate serum concentrations in 12 subjects who received a single 900 mg dose of Theo-

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24 (three 300 mg capsules) under fasting conditions and immediately after a medium-fat (fat content 10 gm) breakfast. Taking Theo-24 with a medium-fat breakfast did not produce any food effect, resulting in no significant differences in either C,,, or AUC (0 to 72) values between fasting and nonfasting states. However, in the same subjects both C,, and AUC (0 to 72) differed significantly when Theo-24 was taken under fasting conditions and immediately after a highfat breakfast (C,,, = 7.7 + 2.6 versus 13.0 -+ 3.2 kg/ml, p < 0.05; AUC (0 to 72) = 216 2 63 versus 272 +- 77 p,g/hr/ml, p < 0.05). The effect of changing the dosing time in relation to a high-fat meal is illustrated in Figs. 10 and 11. In 24 subjects who received a single 900 mg dose of Theo-24 (three 300 mg capsules) immediately after a high-fat breakfast, significantly lower C,,, and AUC (0 to 72) values occurred when the same dose was given 1 hour before this breakfast.

CIRCADIAN VARIATION IN THEOPHYLLINE ABSORPTION After twice-a-day dosing of controlled-release formulations, serum levels of theophylline during the daytime are markedly higher than during the nighttime.“-” This phenomenon has been attributed to circadian variation in absorption of theophylline, because the serum clearance of theophylline is not altered markedly when theophylline is given intravenously during daytime and nighttime.13 Also, pronounced circadian variation in absorption has not been demonstrated with the immediate-release product.

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Tlme, houra FIG. 6. Mean (*SD) serum theophylline concentrationtime curves in six subjects after a single 900 mg dose of Theo-Dur Sprinkle (contents of four 200 mg and two 50 mg capsules mixed with 15 ml applesauce) given under fasting conditions (0) and immediately after a high-fat breakfast (~1.

However, pronounced circadian variation in absorption has been found even with controlled-release products such as Theo-Dur tablets that have not demonstrated important food effect in the single-dose studies conducted in the moming.14%I5 Because the nighttime dose is generally taken shortly before or after a heavy meal and because

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FIG. 8. Mean (*SD) serum theophylline concentrationtime curves in 12 subjects after a single 900 mg dose of Theo-24 (three 300 mg capsules) given under fasting conditions (0) and immediately after a medium-fat breakfast (m). (From Karim A, Burns T, Janky D, Hutwitz A. Clin Pharmacol Ther 1985;38:642.)

posture’6 difference exists at night, we examined” the combined effect of food and posture on absorption of theophylline from a standard controlled-release product, Theo-Dur tablets. Six hundred milligrams of Theo-Dur tablets was administered every 12 hours for 9 days to 18 male nonsmokers. Steady-state serum

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of theophylline C,,, and AUC (0 to 72) in six Sprinkle given under fasting conditions and

concentration-time curves were determined on days 6 and 9 (Figs. 12 and 13). On day 6 the 7 A.M. dose was administered under fasting conditions, and the 7 P.M. dose 1 hour after a typical American evening meal consisting of 168 gm Salisbury steak, 112 gm mashed potatoes, 168 gm green beans, one dinner roll, carrot cake, and 0.24 L milk (approximately 57 gm protlein, 53 gm fat, 72 gm carbohydrate; 1010 calories). On day 9 the 7 A.M. dose was administered under fasting conditions, whereas the 7 P.M. dose was administered after a 5-hour fast, and subjects did not eat for 5 hours thereafter. Mean steady-state serum concentration-time curves in Fig. 12 show that on day 6 the evening meal caused absorption changes with Theo-Dur given at night, resulting in mean nighttime AUC (12 to 24) values approximately 18% lower than the daytime AUC (0 to 12) values. The morning predose serum level was also significantly higher than the evening predose level (Fig. 13). However, when the evening meal was omitted on day 9, then both the morning and evening predose serum levels as well as AUC (0 to 12) and AUC (12 to 24) did not differ significantly. With nighttime dosing, therefore, the food effect may be different because of combined effects of food and posture.‘6 These observations have two important clinical and biopharmaceutical implications: (1) during theophylline therapy with controlled-release products, the morning predose serum levels do not necessarily represent the trough levels (Fig. 13). True trough levels, in fact, frequently occur 0 to 3 hours

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after the second evening dose; (2) in assessing bioavailability of test and reference controlled-release products at steady state, it is desirable to obtain a full 24-hour serum concentration-time curve because for each product the curve after the first dose (0 to 12 hours) may not be identical to that after the second dose ( 12 to 24 hours). CONCLUSIONS IMPLICATIONS

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1. A variety of food-induced absorption changes (food effect) occur with controlled-release formulations of theophylline. These changes include: increase in the rate and extent of absorption, increase in the extent of absorption, decrease in the extent of absorption, decrease in the rate of. absorption, and more variable and erratic absorption. 2. Food effect studies should therefore be done with all controlled-release products of theophylline under optimal conditions with standardized protocols. 3. Optimal experimental conditions to produce food effect include: ingestion of a large, high-fat meal and drug dosing immediately after a high-fat meal. 4. Both the fat content of the meal and the dosing time relative to meal intake are important factors influencing the magnitude of food effect. 5. The food effect occurs with formulations with pH-dependent and pH-independent in vitro dissolution characteristics. 6. With twice-a-day dosing, the nighttime serum

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concentrations tend to be lower than the daytime concentrations. The true trough levels frequently occur 0 to 3 hours after an evening dose rather than immediately before the morning dose. This phenomenon is attributed to combined effects of food and posture on

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FIG. 11. Individual points and mean (*SD) values of theaphylline C,,, and AUC (0 to 72) in 24 subjects after a single 900 mg dose of Theo-24 given inmediately after and 1 hour before a high-fat breakfast. (From Karim A, Burns T, Janky D, Hurwitz A. Clin Pharmacol Ther 1985;38:642.)

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Time, hours FIG. 12. Mean steady-state serum concentration-time curves of theophylline on days 6 and 9 in 18 healthy, male nonsmokers (mean 2 SD [range]; clearance = 0.78 2 0.20 [0.51 to 1.141 mliminlkg and elimination half-life = 6.45 t 1.89 [4.14 to 9.681 hours) after 600 mg every 12 hours dosing with Theo-Dur tablets. Evening dose was given I hour after a meal on day 6 and 5 hours after a meal on day 9. A fast of at least 2 hours was maintained in both cases after evening doses. (From Karim A. Pharmacotherapy 1984;4:192.)

the absorption of theophylline from controlled-release products. 7. If possible, steady-state bioavailability with controlled-release products should be assessed from the entire 24-hour serum concentration-time curve because of possible daytime versus nighttime differences in serum concentrations after twice-a-day dosing. REFERENCES 1. Pedersen S. Dela:y in the absorption rate of theophylline from a sustained release theophylline preparation caused by food. Br J Clin Pharmacol 1981;12:904.

2. Lagas M, Jonkman JHG. Greatly enhanced bioavailability of theopt ylline on postprandial administration of a sustained release tablet. Eur J Clin Pharmacol 1983;24:761. 3. Pedersen S, Moller-Petersen J. Erratic absorption of a slowrelease theophylline sprinkle product. Pediatrics 1984;74:534. 4. Vaughan L, Milavetz G, Hill M, Weinberger M, Hendeles L. Food-induced dose dumping of Theo-24, a “once-daily” slowrelease: theophylline product. Drug Intell Clin Pharm 1984; 185111. 5. Karim A. Theophylline with food: Theo-24. Am Pharm 1985; NS25: 132.

6. Karim A, Bums T, Wearley L, Streicher J, Palmer M. Foodinduced changes in theophylline absorption from controlledrelease formulations. Part I. Substantial increased and de-

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creased absorption with Uniphyl tablets and Theo-Dur Sprinkle. Clin Pharmacol Ther 1985;38:77. Karim A, Bums T, Janky D, Hurwitz A. Food-induced changes in theophylline absorption from controlled-release formulations. Part II. Importance of meal composition and dosing time relative to meal intake in assessing changes in absorption. Clin Pharmacol Ther 1985;38:642. Wearley L, Pagone F, Streicher J, Wickman A, Karim A. Possible in vitro model for explaining the effect of food on the absorption of theophylline from oral controlled release products. Twelfth International Symposium on Controlled Release of Bioactive Materials, July 8-12, 1985, Geneva, Switzerland. Maturu PK, Prasad VK, Worsely WN, Shiu GK, Skelly JP. The influence of high fat breakfast on the bioavailability of theophylline from controlled release formulations-an in vitro explanation. APhA Academy of Pharmaceutical Sciences Thirty-ninth National Meeting, Abstracts of Contributed Papers 1985;15:137. Scott PH. Tabachnik E, MacLeod S, Correia J, Newth C, Levison H. Sustained-release theophylline for childhood asthma: evidence for circadian variation of theophylline pharmacokinetics. J Pediatr 1981;99:476. Taylor DR, Duffin D, Kinney CD, McDevitt DG. Circadian variation in plasma theophylline concentrations during main-

12.

13.

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tenance therapy with a sustained-release preparation in patients with obstructive airways disease. Br J Clin Pharmacol 1984; 18:2i. Coulthard KP, Birkett DJ, Lines DR, Grgurinovich N, Grygiel JJ. Bioavailability and diurnal variation in absorption of sustained release theophylline in asthmatic children. Eur J Clin Pharmacol 1983;25:667. Taylor DR, Duffin D, Kinney CD, McDevitt DG. Investigation of diurnal changes in the disposition of theophylline. Br J Clin Pharmacol 1983;16:416. Leed:s NH, Gal P, Purohit AA, Walter JB. Effect of food on the bloavailability and pattern of release of a sustained-release theophylline tablet. J Clin Pharmacol 1982;22:196. Sips 4P, Edelbrock PM, Kulstad S, et al. Food does not affect bioakailability of theophylline from Theolin Retard. Eur J Clin Pharmacol 1984;26:405. Warren JB, Cuss S, Barnes PJ. Posture and theophylline kinetics. Br J Clin Phatmacol 1985;19:707. Karim A. Commentary on the paper by Weinberger MM: Theophylline QID, TID, BID and now QD? A report on 24-hour dosing with slow-release theophylline formulations with emphasis on analyses of data used to obtain Food and Drug Administration approval for Theo-24. Pharmacotherapy 1984; 4.19’1. ‘