Population Pharmacokinetic Modeling of Intravenous Topiramate in Patients with Epilepsy and Migraine

Abstract Topiramate (TPM) is approved for seizures and migraine prophylaxis and is used off-label for several neuropsychiatric conditions. The available dosage forms, including tablets and sprinkle capsules, are unsuitable for patients who may be unable to take medicine orally. The resulting potential treatment interruptions could have untoward consequences and underscores the importance of developing a parenteral formulation. In this study, we developed a population pharmacokinetic model of a novel, intravenous TPM formulation using data from a study in patients with epilepsy or migraine receiving a single intravenous dose of stable-labeled TPM. In total, 246 TPM concentrations from 20 adult patients were included for model development. A three-compartment pharmacokinetic model with linear elimination fit the concentration-time data best. Simulations for various loading and maintenance regimens for patients with and without enzyme-inducing comedications were performed. The final estimates(95% confidence interval (CI)) for CL (L/h), V1 (L), and the peripheral volumes, V2 and V3 for a 70 kg person were 1.31( 1.01 – 1.53 ), 9.84 ( 8.49 – 11.0 ), 39.1 ( 36.5 – 41.8 )L, and 9.01 ( 6.41 – 44.3 ) respectively. The use of enzyme-inducing co-medication was the only significant covariate, associated with a 63% increase in clearance .Goodness-of-fit plots and visual predictive checks indicate satisfactory model performance and prediction. The simulation results indicate that adjusting doses for patients receiving IV TPM can mitigate the changes in plasma TPM concentrations resulting from enzyme induction. This population pharmacokinetic model for intravenous topiramate can inform dosing decisions for patients with epilepsy when used as either initiation or bridging therapy.