Summary
Currently, theophylline is being used predominantly as sustained-release capsules or tablets. In the mid-seventies the first preparations for use with a dosage interval of 12 hours (twice-daily preparations) were introduced. Since 1983, theophylline preparations that can be given with an interval of 24 hours (once-daily preparations) have become available.
The release of theophylline from some of these products can be influenced (either increased or decreased) by concomitant intake of food. With some preparations the composition of the meal (especially the fat content) has an influence on the degree of effect.
The consequence may be an effect on the rate of absorption or on the amount absorbed, or both simultaneously. This could result in an unexpected shift of the plasma theophylline concentration. Such a shift is therapeutically undesirable, because theophylline has a fairly narrow therapeutic range.
A review is given of those food interactions with the sustained-release theophylline preparations, both twice-daily and once-daily products, that are currently on the world market.
Special attention is paid to the specific (bio)pharmaceutical characteristics of the different products, and to the influence of the composition and timing of the meals. For each preparation the effect of food on the following pharmacokinetic parameters is discussed: area under the plasma concentration-time curve, peak plasma drug concentration and time to reach this peak. Where possible, the results for both adults and children are discussed. There are indications that children are more susceptible to food-effects than adults.
The regulatory aspects are mentioned briefly.
Clinically important effects of food have been observed with the following twice-daily products: ‘Theo-Dur Sprinkle’, ‘Theolair SR’ (= ‘Nuelin SR’) and ‘Theograd’. Pronounced effects could have an even greater impact with once-daily preparations, as the total daily dose will be given at a single time. A particularly sudden release of a major part of the dose (‘dose-dumping’) may result in toxic plasma concentrations. Among these products, clinically important effects in children have been reported with ‘Theo-24’ and ‘Uniphyl’.
Similar content being viewed by others
References
Anderson KE, Conney AH, Kappas A. Nutrition and oxidative drug metabolism in man: relative influence of dietary lipids, carbohydrate and protein. Clinical Pharmacology and Therapeutics 26: 493–501, 1979
Anderson KE, Kappas A. Dietary influences on the metabolism of theophylline and other drugs in humans. In Jonkman et al. (Eds) Sustained release theophylline in the treatment of chronic reversible airways obstruction, pp. 83–90, Excerpta Medica, Amsterdam, 1984
Birkett DJ, Coulthard KP, Lines D, Grgurinovich N. Circadian variation in the absorption of three sustained release theophylline products in asthmatic children and the effect of food on absorption of Somophyllin® C.R.T. British Journal of Clinical Practice 38 (Suppl. 35): 17–23, 1984
Boxenbaum HG. Physiological and pharmacokinetic factors affecting performance of sustained release dosage forms. Drug Development and Industrial Pharmacy 8: 1–25, 1982
Brazier JL, Soubeyrand J, Desage M, Gillet A, Georges D. Influence de l’alimentation sur la cinétique d’une théophylline à action prolongée prise une fois par jour. Acta Therapeutica 11 (Suppl.): 35–47, 1985
Coulthard KP, Birkett DJ, Lines DR, Grgurinovich N, Grygiel JJ. Bioavailability and diurnal variation in absorption of sustained release theophylline in asthmatic children. European Journal of Clinical Pharmacology 25: 667–672, 1983
Crombeen JP, de Blaey CJ. In vitro testing of controlled release theophylline preparations: Theolair®, Theograd® and Theolin®. Pharmaceutisch Weekblad — Scientific Edition 5: 65–69, 1983
Delhotal-Landes B, Flouvat B, Boutin MS, Karpouzas I, Prinseau J. Influence of food on the absorption of theophylline administered in the form of sustained release tablet and microgranules. Biopharmaceutics and Drug Disposition 9: 19–29, 1988
Feldman CH, Hutchinson VE, Pippenger CE, Blumenfeld TA, Feldman BR, et al. Effect of dietary protein and carbohydrate on theophylline metabolism in children. Pediatrics 66: 956–962, 1980
Feldman CH, Hutchinson VE, Sher TH, Feldman BR, Davis WJ. Interaction between nutrition and theophylline metabolism in children. Therapeutic Drug Monitoring 4: 69–76, 1982
Flouvat B, Delhotal-Landes B, Boutin-Pannetier MS. Influence de la nourriture sur la biodisponibilité de la théophylline présentée sous une formulation à libération prolongée (Dilatrane® AP). Thérapie 41: 144–145, 1986
Golub AL, Frost RW, Betlach CJ, Gonzalez MA. Physiologie considerations in drug absorption from the gastrointestinal tract. Journal of Allergy and Clinical Immunology 78: 689–694, 1986
Green ER, Green AW, Lanc R, Slaughter R, Middleton E. Absorption characteristics of sustained release theophylline capsules administered in applesauce. Journal of Pediatrics 98: 832–834, 1981
Hendeles L, Iafrate RP, Weinberger M. A clinical and pharmacokinetic basis for the selection and use of slow release theophylline products. Clinical Pharmacokinetics 9: 95–134, 1984
Hendeles L, Massanari M, Weinberger M. Update on the pharmacodynamics and pharmacokinetics of theophylline. Chest 88 (Suppl.): 103S–111S, 1985
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 87: 758–765, 1985
Hendeles L, Weinberger M. Selection of a slow release theophylline product. Journal of Allergy and Clinical Immunology 78: 743–751, 1986
Hendeles L, Weinberger M. Theophylline product and dosing interval selection for chronic asthma. Journal of Allergy and Clinical Immunology 76: 285–291, 1985
Hendeles L, Weinberger M. Theophylline: ‘state of the art’ review. Pharmacotherapy 3: 2–44, 1983
Hendeles L, Wubbena P, Weinberger M. Food-induced ‘dose-dumping’ of once-a-day theophylline. Lancet 2: 1471, 1984
Hiatt P, Scott P, Hearn D, Krames W, Smolensky M, et al. Effect of dosing time on pharmacokinetics of once daily theophylline in asthmatic children. American Review of Respiratory Diseases 133: A42, 1986
Jonkman JHG, Berg WChr, de Vries K, de Zeeuw RA, Schoenmaker R, et al. Disposition and clinical pharmacokinetics of theophylline after administration of a new sustained release tablet. European Journal of Clinical Pharmacology 21: 39–44, 1981
Jonkman JHG, Grasmeijer G, Holland A. Theophylline disposition after single-dose ingestion of a once-a-day preparation (Dilatrane AP 400mg) with and without breakfast. International Journal of Clinical Pharmacology, Therapy and Toxicology 25: 633–637, 1987.
Jonkman JHG, Schoenmaker R, Grimberg N, de Zeeuw RA. A new in vitro dissolution test for controlled release theophylline tablets. International Journal of Pharmaceutics 8: 153–156, 1981
Jonkman JHG, Smolensky MH. Chronopharmacology of theophylline, with special reference to age. Annual Review of Chronopharmacology 1: 73–76, 1984
Jonkman JHG. The role of food intake on day-night differences in theophylline absorption. Annual Review of Chronopharmacology 3: 161–164, 1986
Jonkman JHG, van der Boon WJV, Balant LP, Le Cotonnec JY. Food reduces the rate but not the extent of the absorption of theophylline from an aqueous solution. European Journal of Clinical Pharmacology 28: 225–227, 1985
Jonkman JHG, van der Boon WJV, Balant LP, Le Cotonnec JY. No effect of food on single dose bioavailability of sustained release theophylline (Sabidal®): a comparison between Sabidal® and choline theophyllinate solution. International Journal of Pharmaceutics 25: 113–117, 1985
Jonkman JHG, van der Boon WJV, Balant LP, Schoenmaker R, Holtkamp A. Chronopharmacokinetics of theophylline after sustained release and intravenous administration to adults. European Journal of Clinical Pharmacology 25: 215–222, 1984
Juan D, Worwag EM, Schoeller DA, Kotake AN, Hughes RL, Frederiksen MC. Effects of dietary protein on theophylline pharmacokinetics and caffeine and aminopyrine breath tests. Clinical Pharmacology and Therapeutics 40: 187–194, 1986
Kappas A, Alvares AP, Anderson KE, Pantuck EJ, Pantuck CB, et al. Effect of charcoal-broiled beef on antipyrine and theophylline metabolism. Clinical Pharmacology and Therapeutics 23: 445–450, 1978
Kappas A, Anderson KE, Conney AH, Alvares AP. Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man. Clinical Pharmacology and Therapeutics 20: 643–653, 1976
Karim A, Burns 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. Clinical Pharmacology and Therapeutics 38: 642–647, 1985a
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 decreased absorption with Uniphyl® tablets and Theo-Dur® Sprinkle. Clinical Pharmacology and Therapeutics 38: 77–83, 1985b
Kehe CR, Ekholm BP, Chann SF, Wick KA, Rhode KA, et al. Comparative absorption of theophylline from Theolair® S.R. and two reference theophylline preparations following multiple doses with food. Current Therapeutic Research 39: 3–7, 1986
Lagas M, Jonkman JHG. Greatly enhanced bioavailability of theophylline on postprandial administration of a sustained release tablet. European Journal of Clinical Pharmacology 24: 761–767, 1983
Lagas M, Jonkman JHG. Influence of food on the rate and extent of absorption of theophylline after single dose oral administration of a controlled release tablet. International Journal of Clinical Pharmacology, Therapy and Toxicology 23: 424–426, 1985
Lagas M, Jonkman JHG. Studies on the delivery mechanisms of theophylline from a sustained release tablet. Drug Development and Industrial Pharmacy 12: 489–506, 1986
Leeder JS, Robertson C, Correia JN, Isles AF, Levison H, et al. Evaluation of serum theophylline concentrations following administration of sustained release beads in applesauce to asthmatic pre-school children. Annals of Allergy 56: 133–137, 1986
Leeds NH, Gal P, Purohit AA, Walter JB. Effect of food on the bioavailability and pattern of release of a sustained release theophylline tablet. Journal of Clinical Pharmacology 22: 196–200, 1982
Leslie S. The Contin delivery system: dosing considerations. Journal of Allergy and Clinical Immunology 78: 768–773, 1986
Maturu PK, Prasad VK, Worsley WN, Shin GK, Skelly JP. Influence of a high fat breakfast on the bioavailability of theophylline controlled release formulations: an in vitro demonstration of an in vivo observation. Journal of Pharmaceutical Sciences 79: 1205–1206, 1986
McEwen J, McMurdo MET, Moreland TA. The effect of food on the pharmacokinetics of controlled release theophylline capsules formulation following multiple dosing. Research and Clinical Forums 10: 47–54, 1988
Melander A. Influence of food on the bioavailability of drugs. Clinical Pharmacokinetics 3: 337–351, 1978
Milavetz G, Vaughan L, Weinberger M, Harris J, Mullenix T. Bioavailability of oral theophylline: single and multiple dose studies of Uniphyl®. Journal of Allergy and Clinical Immunology 77: 146, 1986
Moreland TA, McMurdo MET, McEwen J. The effect of fasting, food and antacid on the pharmacokinetics of controlled release theophylline capsules. Research and Clinical Forums 10: 43–46, 1988
Osman MA, Patel RB, Irwin DS, Welling PG. Absorption of theophylline from enteric coated and sustained release formulations in fasted and non-fasted subjects. Biopharmaceutics and Drug Disposition 4: 63–72, 1983
Pedersen S. Delay in the absorption rate of theophylline from a sustained release theophylline preparation caused by food. British Journal of Clinical Pharmacology 12: 904–905, 1981
Pedersen S, Møller-Petersen J. Erratic absorption of a slow release theophylline sprinkle product. Pediatrics 74: 534–538, 1984
Pedersen S, Møller-Petersen J. Influence of food on the absorption rate and bioavailability of a sustained release theophylline preparation. Allergy 37: 531–534, 1982
Pedersen S, Møller-Petersen J. Influence of food on the absorption of theophylline from a sustained release formulation (Somophyllin®). Clinical Allergy 15: 253–259, 1985
Pedersen S, Steffensen G. Absorption characteristics of once-a-day slow release theophylline preparation in children with asthma. Journal of Pediatrics 110: 953–959, 1987
Pedersen S, Steffensen G. Food and fasting absorption of a single dose of a sustained release theophylline sprinkle formulation in children. Allergy 41: 46–50, 1986
Rivington RN, Calcutt L, Child S, MacLeod JP, Hodder RV, et al. Comparison of morning versus evening dosing with a new once-daily oral theophylline formulation. American Journal of Medicine 79 (Suppl. 6A): 67–72, 1985
Saccar CL, Rocci Jr ML, Mansmann Jr HC. The effect of food on the in vivo mean absorption and dissolution times of two sustained release theophylline (SRT) preparations. Journal of Allergy and Clinical Immunology 77: 146, 1986
Schulz HU, Karlsson S, Sahner-Ahrens I, Steinijans VW, Beier W. Effect of drug intake prior to or after meals on serum theophylline concentrations: single dose studies with Euphylong®. International Journal of Clinical Pharmacology, Therapy and Toxicology 25: 222–228, 1987
Shenfield GM, Hudson BJ, Boutagy JS, Munro IA, Vandenberg RA. Effect of food and tablet division on the absorption of a sustained release preparation of theophylline. Medical Journal of Australia 140: 477–479, 1984
Sips AP, Edelbroek PM, Kulstad S, de Wolff FA, Dijkman JH. Food does not affect the bioavailability of theophylline from Theolin® Retard. European Journal of Clinical Pharmacology 26: 405–407, 1984
Skelly JP, Barr WH, Benet LZ, Doluisio JT, Goldberg AH, et al. Report of the workshop on controlled release dosage forms: issues and controversies. Pharmaceutical Research 4: 75–77, 1987
Smolensky MH, Scott PH, Barnes PJ, Jonkman JHG. The chronopharmacology and chronotherapy of asthma. Annual Review of Chronopharmacology 2: 229–273, 1985
Spector SL. Advantages and disadvantages of 24-hour theophylline. Journal of Allergy and Clinical Immunology 76: 302–311, 1985
Spector SL, Rohr AS, Rachelefsky GS, Katz RM, Siegel SC, et al. The effect of food on once daily Theo-Dur® in asthmatic subjects. Journal of Allergy and Clinical Immunology 75: 105, 1985
Spector SS. Theophylline once-a-day dosage. Chest 90: 623–625, 1986
Steffensen G, Pedersen S. Food induced changes in theophylline absorption from a once-a-day theophylline product. British Journal of Clinical Pharmacology 22: 571–577, 1986
Tang-Liu DDS, Williams RL, Riegelman S. Non-linear theophylline elimination. Clinical Pharmacology and Therapeutics 31: 358–369, 1982
Thompson PJ, Kemp MW, McAllister WAC, Turner-Warwick M. Slow release theophylline in patients with airways obstruction with particular reference to the effects of food upon serum levels. British Journal of Diseases of the Chest 77: 293–298, 1983
Thompson PJ, Skypala I, Dawson S, McAllister WAC, Turner-Warwick M. The effect of diet upon serum concentrations of theophylline. British Journal of Clinical Pharmacology 16: 267–270, 1983
Tinkelman DG, Edelman L, Decouto J, Maloch LD, Spangler DL. The effect of diet on the metabolism of long acting theophylline. Annals of Allergy 54: 280–283, 1985
Vaughan L, Milavetz G, Hill M, Weinberger M, Hendeles L. Food-induced ‘dose-dumping’ of Theo-24, a once-daily slow release theophylline product. Drug Intelligence and Clinical Pharmacy 18: 510, 1984
Wagner JG. Theophylline: pooled Michael is-Menten parameters (Vmax and Km) and implications. Clinical Pharmacokinetics 10: 432–442, 1985
Warren JB, Cuss F, Barnes PJ. Posture and theophylline kinetics. British Journal of Clinical Pharmacology 19: 707–709, 1985
Weinberger M. Clinical and pharmacokinetic concerns of 24-hour dosing with theophylline. Annals of Allergy 56: 2–8, 1986
Welling PG. Influence of food and diet on gastrointestinal drug absorption — a review. Journal of Pharmacokinetics and Biopharmaceutics 5: 291–334, 1977
Welling PG, Lyons LL, Craig WA, Trochta GA. Influence of diet and fluid on bioavailability of theophylline. Clinical Pharmacology and Therapeutics 17: 475–480, 1975
Author information
Authors and Affiliations
Additional information
All products in quotes (e.g. ‘Theo-Dur’) are registered trade marks of the manufacturers listed.
Rights and permissions
About this article
Cite this article
Jonkman, J.H.G. Food Interactions with Sustained-Release Theophylline Preparations. Clin-Pharmacokinet 16, 162–179 (1989). https://doi.org/10.2165/00003088-198916030-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-198916030-00003