ORAL FORMULATIONS OF ADEFOVIR DIPIVOXIL - IN-VITRO DISSOLUTION AND IN-VIVO BIOAVAILABILITY IN DOGS

The effect of formulation on oral bioavailability of the antiviral nuc leotide analogue adefovir from the prodrug adefovir dipivoxil was exam ined in beagle dogs. A suspension formulation of adefovir dipivoxil gr anules was administered to five fasted male beagle dogs (250 mg prodru g per dog; 135.7 mg-equiv of adefovir per dog). Tablets prepared from the same granulation (batch B94) were administered at 2 x 125 mg prodr ug per dog, in addition, the same tablets were administered to dogs in the fed state or following pentagastrin pretreatment. Two further tab let batches (H94 and D501) with slight formulation changes were also e valuated in pentagastrin pretreated dogs (n = 5). Concentrations of ad efovir in plasma were determined by HPLC following fluorescence deriva tization. Tablet dissolution was examined at pH 2.0. One batch of adef ovir dipivoxil tablets showed a 5-fold slower dissolution rate in vitr o (B94 = H94 much greater than D501). Adefovir dipivoxil was completel y converted to adefovir following oral absorption in dogs. The oral bi oavailability of adefovir from the suspension was 35.0 +/- 8.9%. The o ral bioavailability of adefovir from the tablet formulation was 34.7 /- 10.3%, 37.2 +/- 4.5%, and 44.9 +/- 5.9% in fasted dogs fed dogs and tasted dogs pretreated with pentagastrin, respectively. All three tab let batches had equivalent bioavailability in dogs. Oral bioavailabili ty oi adefovir from the prodrug in dogs (35-46%) was unaffected by for mulation, food, or the acidic pH of the gastrointestinal tract. In vit ro dissolution of adefovir dipivoxil tablets did not correlate with or al bioavailability. Oral bioavailability of adefovir dipivoxil appears to be limited by low permeability and biological conversion of the pr odrug to adefovir.