| Abstract: | The anticonvulsant ameltolide (LY201116) is a novel potential therapy for the treatment of canine epilepsy. Eight dogs were administered five different oral doses of ameltolide and clinical scoring of the maximal electroshock (MES) induced seizures at 3 and 24 h postdosing were determined in two separate crossover design studies. Plasma ameltolide concentrations were determined at the time of seizures in all dogs and complete plasma concentration‐time profiles were also determined in a separate study. A nonlinear mixed effects PK/PD model was fit to the resulting data. A one compartment open model with first order absorption was determined to best fit the ameltolide pharmacokinetics. An effect compartment with a cumulative logistic regression equation was used to establish the PK/PD relationship. The mean bioavailability normalized volume of distribution and the elimination half‐life were estimated at 1.20 L/kg and 5.46 h, respectively. The fitted model estimated that from 2 to 15 h following a single 3 mg/kg oral ameltolide dose the mean probability of obtaining a 1 unit reduction in the seizure clinical score severity was greater than 0.80. The utilized PK/PD analysis combined with the canine MES model allowed for the rapid and efficient determination of the plasma ameltolide concentration‐anticonvulsant relationship preclinically in dogs. |
