Comparison of inter- and intra-subject variation in oral absorption of theophylline from sustained-release products

A comparative study of inter- and intra-subject variation in the bioavailability of theophylline from two commercial sustained-release dosage forms (a beaded capsule and a tablet formulation) was performed in 12 healthy adult volunteers. The disposition kinetics of theophylline was characterized in each subject following a single 250 mg oral dose of a fully bioavailable liquid formulation. Duplicate single dose studies of each of the two sustained-release products were then performed on 4 separate occasions in a randomized crossover fashion. On the average, the extent of theophylline bioavailability from the two sustained-release dosage forms was equivalent and essentially complete as compared to that from the liquid formulation. Both sustained-release formulations exhibited reasonable consistency in the extent of bioavailability when tested on two different trial days in a given subject (the mean percentage difference in extent of absorption was 11.5 ± 8.3% for the beaded capsule and 11.8 ± 12.3% for the tablet). The rate of theophylline absorption from the beaded capsule formulation was more rapid than from the tablet formulation as indicated by an earlier time to reach peak serum concentration (6.0 ± 1.9 vs 8.9 ± 2.5 h). Individual time course of cumulative absorption from the sustained-release formulations was determined using the Wagner-Nelson procedure. The overall variability in the cumulative absorption profile was greater for the tablet as compared to the capsule formulation. More significant was the fact that within each subject the absorption profiles were less reproducible between trials with the tablet as compared to the capsule. Dose-to-dose variation in the release/absorption kinetics of theophylline from these sustained-release products may lead to unpredictable fluctuations in steady-state serum theophylline concentration-time profiles during chronic drug administration.