Abstracts

Rationale: Carbamazepine (CBZ) is a well established anti-epileptic therapy with a favorable safety profile. A new intravenous (IV) formulation of CBZ, formulated in a cyclodextrin matrix Captisol®, is currently under development as IV replacement therapy in patients for whom administration of oral CBZ is temporarily not feasible. Methods: The current study is a multi-center, sequential, open-label Phase I study to assess the safety, tolerability and comparative pharmacokinetics (PK) of IV and oral CBZ in adult epileptic patients currently stable on a fixed oral CBZ dose of 400 to 2000 mg/day. Subjects were infused over 30 or 15 minutes, with two additional cohorts receiving an extra day of 5 minute or bolus infusions. The IV infusions were administered every 6 hours for 7 consecutive days to allow for evaluation of IV CBZ pharmacokinetics at steady-state. Blood samples were collected for PK analysis. Based upon a previous IV versus oral study, mean CBZ bioavailability was estimated to be 70%; thus the IV CBZ total daily dose for the current study is given at 70% of the patients' oral CBZ total daily dose. Each patient who completed the study received a minimum of 28 infusions over a seven day period while confined for at least ten days. Rigorous cardiac and blood pressure monitoring included 3-lead telemetry, serial ECGs, Holter monitoring and frequent orthostatic measurements of pulse and blood pressure. Results: To date, 78 patients have received 2,143 infusions of CBZ. There is a total of 5 cardiac related adverse events; none were serious. Events of heart palpatations, premature ventricular contractions, tachycardia, and 2nd degree sino-atrial exit block with a two second pause were experienced by 4 separate patients. These events resolved spontaneously and were considered unrelated to study drug by the Principal Investigators. One patient experienced Multi-Focal Atrial Tachycardia that was considered to be possibly drug related and resolved spontaneously. Full analysis of 12-lead Holter data is pending. Conclusions: Preliminary data demonstrates that intravenous carbamazepine administered at 70% of oral dosing is well tolerated without clinically significant cardiac adverse events when administered in a closely monitored setting.