PHARMACOKINETICS AND BIOAVAILABILITY OF TOPIRAMATE IN THE BEAGLE DOG

Male and female beagle dogs showed rapid absorption following oral adm inistration of single oral gavage (40 mg/kg) and single or multiple (1 5 days) oral capsule (10, 40, and 150 mg/kg) doses of the novel antico nvulsant drug, topiramate, with the peak plasma concentration (C-max) occurring between 0.6 and 3.8 hr. The absolute bioavailability of an o ral dose of topiramate was estimated to be in the range of 27-59%, dep ending on the formulation. The mean topiramate (C-max) values increase d in a dose-proportional manner for both single (9.2-137.7 mu g/ml) an d multiple (10.3-145.2 mu g/ml) oral capsule administrations, whereas the corresponding area under the plasma concentration vs. time curve ( AUG) values increased in a dose-related but nonproportional manner for both single (51-1131 mu g.hr/ml) and multiple (54-858 mu g.hr/ml) dos es. Over the 10-150 mg/kg dosing range, oral plasma clearance and term inal half-life values were found to be 2.4-3.6 ml/min/kg and 2.6-3.7 h r following a single oral administration, and 3.0-4.2 ml/ min/kg and 2 .0-3.8 hr after multiple doses. There were no significant differences between the pharmacokinetic parameters calculated following the first and fifteenth daily doses of topiramate at the 10 and 40 mg/kg levels, indicating that there was no accumulation and no autoinduction or inh ibition of enzymes that metabolize topiramate resulting from multiple dosing at these levels. A slight (24%) decrease in AUC was observed at the 150 mg/kg level after the fifteenth daily dose. The extent of abs orption of topiramate following a single 40 mg/kg oral solution dose a dministered by gavage (as represented by AUG) was approximately 2-fold greater than that for the dry-filled capsule formulation at that dose (339-346 vs. 190 mu g.hr/ml). The apparent volume of distribution fol lowing a single intravenous 10 mg/kg dose of topiramate in the male do g was 0.63 liters/kg, which approximates the volume of total body wate r. The plasma protein binding was found to be low by equilibrium dialy sis: 8-13% of added topiramate over the range of 1-168 mu g/ml. A high -affinity, low-capacity binding site for topiramate was observed in do g erythrocytes, which had a dissociation constant of 0.27 mu g/ml (0.8 0 mu M) and a binding capacity of 10.8 mu g/ml.