Selection of a slow-release theophylline product

Abstract

Slow-release formulations of theophylline, if absorbed completely, consistently, and at a sufficiently 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, safety, and 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 of food, depending on as yet unidentified but specific formulation 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 theophylline from the formulation, selection of a product and dosing interval needs to be an individualized clinical decision independent of marketing or regulatory influences. Most formulations with claims for twice-daily dosing cannot reliably maintain fluctuations in serum concentration whereby 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 approved formulations unless taken after food; one, in fact, has such a large increase in rate and extent of absorption when taken with food that its postprandial absorption characteristics are aptly described as dose-dumping.