Comparative bioavailability of two sustained-release theophylline formulations in the dog

Abstract

The kinetics of two sustained-release theophylline formulations, Theo-Dur®(Recordati, Milano, Italy) and Diffumal®(Malesci, Firenze, Italy) were studied in eight beagle dogs. In a first part of the study each animal was injected intravenously with aminophylline dihydrate, Aminomal®(Malesci, Firenze, Italy), in order to determine the absolute bioavailability of the two sustained-release theophylline formulations orally administered to the dogs in the second experimental phase, over a period of 9 days, following a balanced two-period cross-over design. Assays for theophylline were performed by high performance liquid chromatography and the pharmacokinetic analysis was performed using the non-compartmental method. The principle of superposition was then applied to predict multiple dose plasma concentrations from experimental single dose data. No significant differences between the two preparations were found with respect to the main pharmacokinetic parameters, showing that the two preparations are bioequivalent. The fact that the differences between experimental and predicted results were not statistically significant allows us to conclude that multiple dose steady state plasma theophylline concentration in the dog can be predicted from experimental single dose data. Furthermore, after repeated treatment, both Diffumal®and Theo-Dur®, given twice daily are able to maintain therapeutic (5–20 mg ml−1) plasma theophylline concentrations in the dog.