Abstracts

Rationale: Carbamazepine (CBZ) is a widely prescribed, well established antiepileptic therapy. A new intravenous (IV) formulation of CBZ, formulated in a cyclodextrin matrix, Captisol®, is under development. This formulation will be an alternative 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. Pharmacokinetic data of patients given IV infusions over 30, 15, and 5 minutes (or bolus) infusion was collected. The IV infusions were administered every 6 hours for 7 consecutive days to allow for evaluation of pharmacokinetics at steady state. Based upon a previous IV versus oral study, mean CBZ bioavailability was estimated to be 70%; thus the IV 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 7 days while in a closely monitored setting. All patients had a detailed neurological history and physical exam prior to entry into the study at Day -28 and again at Study Day 8. A brief neurological exam was performed during the Lead-In period at Day -14 and every day during the confinement period from Day -1 through Day 7. The brief neurological exam was also perfomred at Study Day 22 or at final visit. Patient completion of the Dosing and Seizure Diary occured at Study Day -28, -21, -14, -7, -1, and Day 22 or day of final visit. Monitoring of patient Dosing and Seizure Diary occured at Study Day -21, -14, -7, -1 and Day 22 or final visit. Adverse event assessments were collected from Study Day -28 through and including Study Day 38. Results: Currently 78 patients have received 2,143 infusions of CBZ. There were 18 Nervous System adverse events; none were serious. Ten adverse events of dizziness were reported; severity was mild (8), moderate (1), or unknown (1). Five adverse events of headache were also reported; severity was mild (3) to moderate (2). Other adverse events included migraine (1) of mild severity, somnolence (1) of mild severity and partial simple seizure (1). This seizure was described as myoclonic type, mild in severity, and new for that patient. Conclusions: Preliminary data demonstrates that intravenous carbamazepine at 70% of oral dosing is well tolerated without clinically significant adverse events of the nervous system when administered in a closely monitored setting.