Therapeutic Equivalence of a Generic Slow‐Release Theophylline Tablet

Abstract

Study Objective. To evaluate the relative bioavailability and clinical efficacy of two slow‐release theophylline products.Design. Randomized, double‐blind, crossover trial.Setting. A university‐affiliated clinical research center.Patients. Fourteen adults with asthma.Interventions. The patients received a generic slow‐release theophylline tablet or Theo‐Dur at bedtime for 5 nights.Measurements and Main Results. Serum drug concentrations were measured after the last dose. Attenuation of exercise‐induced bronchospasm (EIB) was included as a surrogate for efficacy. There was no significant difference in extent of absorption. The mean differences between the generic product and Theo‐Dur in area under the curve was −13.9 μg/ml‐hr−1 (95% CI −41 to 12.9, p=0.3) and in peak concentration (Cmax), −0.5 μg/ml (95% CI −1.7 to 2.7, p=0.6). In contrast, the generic product was absorbed more rapidly; the mean differences in the time to peak concentration (Tmax) was −3.0 hours (95% CI −4.3 to −1.7, p=0.0003), in trough concentration (Cmin), −0.9 μg/ml (95% CI −1.9 to −0.01, p=0.05), and in fluctuation between Cmax and Cmm, +128% (95% CI 40 to 217, p=0.008). Neither product effectively attenuated EIB, since mean serum concentrations during the exercise challenges were unexpectedly below 10 μg/ml after both products.Conclusion. These two products are not bioequivalent, but the difference in absorption rates is unlikely to be clinically important in most patients (i.e., they are therapeutic equivalents).