Abstracts

Rationale: Topiramate (TPM) is a widely prescribed antiepileptic drug. An investigational intravenous (IV) formulation of TPM solubilzed in a cyclodextrin matrix, Captisol , is being developed with the long-term goal of evaluating its safety and efficacy in neonatal seizures. However, pharmacokinetics (PK) and safety must first be demonstrated in adults. The aims of this study were to determine the safety and PK of TPM under steady-state condition in adult patients on maintenance therapy. Methods: Twenty patients with epilepsy or migraine headaches completed the study. All patients were on stable, maintenance TPM therapy. The study was conducted at the University of Minnesota General Clinical Research Center. On the day of the study, patients had a brief physical and neurological examination, an EKG, and a battery of lab tests. Patients were given 25 mgs of a stable-labeled (SL) IV TPM over 10 minutes followed by their usual oral TPM morning dose. Blood samples were taken just prior to IV TPM administration and serially for 96 hours after dosing. TPM and SL-TPM were measured using a validated LC-MS method. Concentration-time data was analyzed using a noncompartmental approach with WinNonlin 5.2. Results: Preliminary PK analysis has been completed on all patients. The mean ( SD) bioavailability was 95 26%, half-life was 29.3 11.3 hours, distribution volume was 0.81 0.26 L/Kg, and clearance was 1.95 1.02 L/hr. Seven patients experienced one or more minor adverse events: nausea and vomiting, tingling around the lips, paresthesia in the arms and legs, and one case of a vasovagal response with IV catheter placement. Four patients with uncontrolled epilepsy experienced a typical seizure during the study. No changes in heart rate, blood pressure, EKG, or infusion site reactions were observed. Conclusions: Our preliminary results provide previously unreported information about IV TPM disposition and adverse effects. The infusion of small doses over 10 minutes appears to be safe. Oral absorption is approximately 100%, indicating that patients could be given the same dose IV as they are taking orally. The steady-state TPM half life appears longer than previously reported, supporting once or twice daily administration. Lastly, the distribution volume of approximately 0.8 L/Kg with minimal variability permits calculation of IV loading doses to quickly, accurately, and safely attain targeted TPM concentrations. Results from this pilot study will inform the design of subsequent studies, including controlled clinical trials intended to determine the efficacy and safety of IV TPM for neonatal seizures. This study was supported by a grant from the FDA Orphan Grants program-R01 FD003540-01. CyDex Pharmaceuticals and the Epilepsy Research Foundation provided grants that supported preparation of the IV TPM formulation.