Comparative bioavailability of three oral formulations of sustained release theophylline in healthy human subjects

Objective: To determine the bioequivalence of two marketed test formulations (A, B) as compared to a reference formulation (R) of slow release theophylline in healthy volunteers.
Material and Methods: The study was conducted as an open label, balanced, randomized, three-treatment, three-period, three-sequence single-dose crossover study to determine the bioequivalence of Phylobid 200 mg SR tablets (A) and Theobid 200 mg SR tablets (B) as compared to Theostan CR 200 mg capsule (R) under fasting conditions. A group of 12 healthy, adult, male human subjects participated in this study. The bioavailability was compared using pharmacokinetic parameters C_max, T_max, AUC_0-t, and AUC_0-∞. Moreover, the 90% confidence interval (CI) for the ratio of logarithmic transformed C_max, AUC_0-t and AUC_0-∞ was also used to determine bioequivalence. A washout period of seven days was kept between each study period. Serial blood samples were collected at 0, 0.5, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21 and 24 h during each study.
Results: The 90% CI for the log transformed data forC_max, AUC_0-t, and AUC_0-∞ for both the test products fell outside the prescribed limits of bioequivalence for narrow therapeutic index drugs i.e. 90-111%. The T/R (test/reference) ratio of product A was quite close to the prescribed limits of bioequivalence (95-105%), while for product B the T/R ratio was not satisfactory.
Conclusions: None of the test products of theophylline were bioequivalent to the reference product. The finding is of special significance since substitution of one brand of theophylline, a drug with a narrow therapeutic index, with another brand may result in sub-therapeutic response in patients.