Kc. Cundy et al., ORAL FORMULATIONS OF ADEFOVIR DIPIVOXIL - IN-VITRO DISSOLUTION AND IN-VIVO BIOAVAILABILITY IN DOGS, Journal of pharmaceutical sciences, 86(12), 1997, pp. 1334-1338
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.