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Therapeutic equivalence of a generic slow-release theophylline tablet
L Hendeles1, A L Breton, R Beaty
1College of Pharmacy, Department of Pediatrics, University of Florida, Gainesville, USA.
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 micrograms/ml.hr-1 (95% CI -41 to 12.9, p = 0.3) and in peak concentration (Cmax), -0.5 microgram/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 microgram/ml (95% CI -1.9 to -0.01, p = 0.05), and in fluctuation between Cmax and Cmin, +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 micrograms/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).