Abstracts

Rationale: Topiramate (TPM) is a widely prescribed antiepileptic drug. An 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. Prior to using an investigational drug in children and neonates, pharmacokinetics (PK) and safety must be demonstrated in adults. The aims of this study are to determine in adult patients on maintenance therapy the safety and steady-state PK of orally and IV TPM. Methods: Eleven of 20 patients have completed the study. Patients were recruited from epilepsy and migraine clinics at Fairview University Medical Center, MINCEP Epilepsy Care, and other neurology clinics in the Minneapolis-St. Paul area. All patients were in good health except for their migraine headaches or epilepsy and 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 held their morning TPM dose until they were admitted to the research center. Following admission, patients had a brief physical and neurological examination, EKG, and battery of lab tests including hemoglobin levels. Patients were given 25 mgs of a stable-labeled (SL) IV TPM over 10 minutes followed by their usual morning dose. The use of SL methodology allows simultaneous administration of oral and IV TPM for determination of bioavailability. Plasma samples were taken just prior to IV TPM administration and 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 seven patients. The mean bioavailability is 105.14% (SD=13.09%). The mean half-life is 36.68 hours (SD=12.4). The volume of distribution is 0.73 L/kg (SD=0.05). The mean clearance is 1.24 L/hr (SD=0.25). Four patients experienced an adverse during the study. There was one case each of a vasovagal response with IV catheter placement, nausea and vomiting, a seizure, and paresthesia in the arms and legs. Conclusions: The preliminary results from this study provide previously unreported information about oral and IV TPM. 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 half-life of TPM appears longer than previously reported, supporting twice daily administration. Lastly, the distribution volume of approximately 0.7 L/kg provides a means to quickly and safely attain drug concentrations using IV TPM as a loading dose. 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 neonatal seizures. This study was supported by grants from the Epilepsy Research Foundation and the FDA Orphan Products Grants Program #1RO1FD003540-01