Food Interactions with Sustained-Release Theophylline Preparations1

Abstract

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'.

The influence of food on the absorption and metabolism of drugs: an update

“…This effect may be on the rate of absorption or on the amount absorbed, or both. This could cause an unexpected shift of the plasma theophylline concentration which is not a desirable occurrence since theophylline has a fairly narrow therapeutic range (18). This important information should be extrapolated to the development of other sustainedrelease formulations of drugs.…”

Adverse Reactions and Interactions with Theophylline

“…Viral infections such as hepatitis and influenza, and certain vaccinations, are believed to indirectly inhibit theophylline metabolism (Feinstein & Miles 1985;Koren & Greenwald 1985;Kraemer et al 1982;Russo 1979); an absolute or relative deficiency of dietary protein may also have a similar result (Kappas et al 1976). A number of drug interactions may contribute to theophylline toxicity (see below), and certain sustained release preparations have recently been imDrug Sq (ety 5 (4) 1990 plicated as a potential cause through rapid release of the entire dose (dose dumping) when taken with food (Hendeles et al 1985b;Jonkman 1989;Steffensen & Pedersen 1986). It is not clear whether the availability of these newer formulations has actually resulted in any increase in the incidence of theophylline toxicity.…”

International Harmonization of Regulatory Requirements for Average Bioequivalence and Current Issues in Individual Bioequivalence

“…This was essentially confirmed during the BioInternational '92 session on food studies in the case of generic formulations (9). Such studies are definitely necessary, for example, in the case of sustained-release theophylline formulations where extreme food effects in both directions (decrease and increase of bioavailability) have been demonstrated (20). It is still a matter of controversy whether they are necessary for controlled-release formulations in general.…”