Effect of Chronic Administration of Phenobarbital, or Bromide, on Pharmacokinetics of Levetiracetam in Dogs with Epilepsy

BackgroundLevetiracetam (LEV) is a common add-on antiepileptic drug (AED) in dogs with refractory seizures. Concurrent phenobarbital administration alters the disposition of LEV in healthy dogs. Hypothesis/ObjectivesTo evaluate the pharmacokinetics of LEV in dogs with epilepsy when administered concurrently with conventional AEDs. AnimalsEighteen client-owned dogs on maintenance treatment with LEV and phenobarbital (PB group, n=6), LEV and bromide (BR group, n=6) or LEV, phenobarbital and bromide (PB-BR group, n=6). MethodsProspective pharmacokinetic study. Blood samples were collected at 0, 1, 2, 4, and 6hours after LEV administration. Plasma LEV concentrations were determined by high-pressure liquid chromatography. To account for dose differences among dogs, LEV concentrations were normalized to the mean study dose (26.4mg/kg). Pharmacokinetic analysis was performed on adjusted concentrations, using a noncompartmental method, and area-under-the-curve (AUC) calculated to the last measured time point. ResultsCompared to the PB and PB-BR groups, the BR group had significantly higher peak concentration (C-max) (73.424.0 versus 37.5 +/- 13.7 and 26.5 +/- 8.96g/mL, respectively, P<.001) and AUC (329 +/- 114 versus 140 +/- 64.7 and 98.7 +/- 42.2h*g/mL, respectively, P<.001), and significantly lower clearance (CL/F) (71.8 +/- 22.1 versus 187 +/- 81.9 and 269 +/- 127mL/h/kg, respectively, P=.028). Conclusions and Clinical ImportanceConcurrent administration of PB alone or in combination with bromide increases LEV clearance in epileptic dogs compared to concurrent administration of bromide alone. Dosage increases might be indicated when utilizing LEV as add-on treatment with phenobarbital in dogs.