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.

Dosing intervals for slow-release theophylline preparations depend on the rate of formulation absorption, the rate of patient elimination, and clinically acceptable fluctuations in serum concentration. Three products, two new to the United States market, have received approval by the Food and Drug Administration (FDA) for 24-hour dosing claims. Data submitted to the FDA for Theo-24 (Searle) suggest slow but incomplete absorption in single-dose studies, and multiple-dose studies confirm incomplete absorption relative to plain theophylline tablets. Fluctuations in serum concentration expressed as a percentage of the trough value at steady state with Theo-24 given once daily in the morning ranged from 48 to 1371% among 18 subjects; 13 of the 18 had greater than 100% fluctuation, which is the upper limit for fluctuations that can stay within the 10- to 20-micrograms/ml therapeutic range. Among another 18 subjects with somewhat slower and less variable rates of elimination, fluctuations ranged from 40-168% at steady state, with 4 of 18 greater than 100% during daily dosing with Theo-24; all subjects had fluctuations less than 100% (39-92%) when they were given Theo-dur tablets every 12 hours. Theo-dur tablets have also received FDA approval for once daily administrations, but only 1 of 14 subjects in a submitted study had fluctuations less than 100% and thus was able to stay within the therapeutic range. No data were available on the absorption of Uniphyl, also approved for once-daily dosing, but large fluctuations in serum concentration are apparent from advertisements for the European product Uniphyllin, and are also suggested by presentations on Uniphyl at a recent scientific meeting. Current standards for receiving FDA approval for 24-hour dosing appear to be inconsistent with the pharmacodynamics and pharmacokinetics of theophylline and fail to consider the greater risks from variability in absorption when a single, large daily dose is taken.