Influence of hyperlipidic food on the kinetics of slow-release formulations of theophylline

Summary

A cross-over study of kinetics has been undertaken in 12 healthy adults volunteers using two sustained-release theophylline products that allow once a day dosing (Theo-Dur tablets and Dilatrane A.P. bead filled capsules) to compare the i.v. pharmacokinetic profiles when taken with an hyperlipidic meal and a balanced standard meal. Each subject took part in four phases in randomised order, corresponding to all possible combinations of the products and the types of meal. Each phase involved a single dose of 9 to 11 mg·kg⁻¹ theophylline administered at 20.00 h, at the beginning of the meal, with 100 ml water.

The two formulations were found to be bioequivalent with both types of meal. Taken with a balanced meal, the mean parameters were similar; for Theo-Dur and Dilatrane A.P. they were respectively:

C_max: 11.32 mg·l⁻¹ which plateaued from 8 to 10 h after dosing and 10.9 mg·l⁻¹, which plateaued after 6 to 10 h; AUC 230 mg·h·l⁻¹ and 220 mg·h·l⁻¹; and MRT 18.2 h and 17.7 h. After the hyperlipidic meal the values for Theo-Dur and Dilatrane A.P. respectively, were: C_max 10.9 mg·l⁻¹ at 12 h and 11.3 mg·l⁻¹ at 10 h; AUC 237 mg·h·l⁻¹ and 227 mg·h·l⁻¹; and MRT 19.2 h and 18.9 h.

In spite of a decrease in the absorption rate, which led to a shift to the right of about 2 h of the plasma concentration-time curve, the bioavailability of both formulations were not significantly modified by a hyperlipidic meal as compared to a balanced meal. The shift of the curve with fatty food was not clinically important, as there was no dumping effect.

The main difference between the two formulations was seen during the absorption phase, which was linear and less variable with Dilatrane A.P. and sigmoidal with Theo-Dur. This was observed with both types of meal.