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

The kinetics of two sustained-release theophylline formulations, Theo-Dur(R ) (Recordati, Milano, Italy) and Diffumal(R) (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(R) (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 perfo rmed by high performance liquid chromatography and the pharmacokinetic anal ysis was performed using the non-compartmental method. The principle of sup erposition 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 parame ters, showing that the two preparations are bioequivalent. The fact that th e differences between experimental and predicted results were not statistic ally significant allows us to conclude that multiple dose steady state plas ma theophylline concentration in the dog can be predicted from experimental single dose data. Furthermore, after repeated treatment, both Diffumal(R) and Theo-Dur(R), given twice daily are able to maintain therapeutic (5-20 m g ml(-1)) plasma theophylline concentrations in the dog. (C) 1998 The Itali an Pharmacological Society.