Abstracts

Rationale: Topiramate (TPM) is a widely prescribed antiepileptic drug. An intravenous (IV) formulation of TPM, solubilized 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 IV TPM formulation in children and neonates, the pharmacokinetics (PK) and safety of the formulation must be determined in adults. The immediate aims of this study were to characterized the PK and safety of IV and orally administered TPM, using clinically relevant doses, in healthy volunteers. Methods: This study utilized a two-way crossover design involving administration single oral and IV TPM doses to 12 adult volunteers. Two subjects received 50 mg of IV TPM over 15 min and 50 mg of oral TPM following a 2 week washout period. The remaining 10 volunteers received 100 mg of IV and oral TPM using the same protocol. Subjects were admitted to Prism Research, a clinical research facility, the day before the studies. Subjects underwent physical and neurological examinations, had EKG recordings and routine laboratory tests. Subjects remained in the facility for 24 hr. for collection of PK blood samples and safety assessments. Additional blood samples were collected and assessments performed at 48, 72, 96, and 120 hr after dosing. Plasma TPM concentrations were measured using a LC-MS method. Concentration-time data was analyzed using a noncompartmental approach with WinNonLin 5.2. Results: All subjects completed the study. The mean ( SD) bioavailability was 109 10.8%. Half-life, distribution volume, and clearance following IV and oral dosing were 42.3 6.2 and 41.2 7.5 hrs, 1.06 0.26 and 0.94 0.24 L/kg, and 1.33 0.26 and 1.22 0.26 L/hr, respectively. No changes in heart rate, blood pressure, EKG, or infusion site reactions were observed. Mild cognitive adverse events and ataxia occurred between dosing and 2 hr post dose and resolved by 4 hr regardless of route. Many subjects on onset of CNS effects during the 15 min IV infusions. Conclusions: The results from this study provide new information about TPM disposition. In healthy adults, oral TPM is bioequivalent to IV TPM. The extended half-life following IV and oral dosing indicates TPM can be given once daily in many patients not taking enzyme inducing medications. Minimal variability in the distribution volume permits use of loading doses to rapidly attain targeted concentration. Mild, but detectable, neurological effects occurred during the infusion demonstrating that TPM quickly enters into the brain. Intravenous infusion of 50 to 100 mg over 15 min appears to be safe. Results from this pilot study will inform the design of subsequent studies in children and newborns, 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 New Therapy Grant Program, Epilepsy Research Foundation. CyDex Pharmaceuticals provided grant to support preparation of the IV TPM formulation.