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

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 interruption could have untoward consequences and underscore 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 who received a single intravenous dose of stable-isotope-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 doses in 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), 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. Pharmacokinetic simulations indicated that IV TPM loading doses do not require adjustment when used as a replacement for interrupted oral therapy. This population pharmacokinetic model for intravenous topiramate can inform dosing decisions for patients with epilepsy when used as either initiation or bridging therapy.