Abstracts

Rationale: Carbamazepine (CBZ) is a widely prescribed, well-established antiepileptic therapy. A new intravenous (IV) formulation of CBZ, solubilized 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 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 patients with epilepsy stabilized on a fixed oral CBZ dose of 400-2000 mg/day. Based on 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 patients’ oral CBZ total daily dose. Patients arrive at the research unit on Day -1 already on maintenance oral CBZ therapy; the following day, Day 0, patients continue on oral therapy and have extensive blood sampling to determine the area under the concentration-time curve (AUC) over a dosing interval for CBZ and CBZ-10, 11-epoxide (CBZ-E), the active metabolite. IV CBZ infusions are then administered over 30- or 15-minutes Q6h for seven consecutive days (study Days 1-7). On Days 1 and 7 extensive blood sampling is conducted over the 1st six hour IV CBZ dosing interval for measurement of CBZ and CBZ-E AUCs. Results: Preliminary PK data from 48 evaluable patients showed IV CBZ infused over 30- or 15-minutes led to Cmin concentrations and overall exposures (AUC 0-24 hrs) of CBZ at steady-state that were similar to those seen following oral CBZ therapy at steady-state. The mean daily oral and IV dose of CBZ for patients in this interim analysis was 937.5 mg/day and 656.1 mg/day, respectively. The mean (% CV) steady-state Cmin CBZ concentration during oral administration (Day 0) was 6.77 (CV=30.7%) µg/mL, similar to 5.95 (CV=25.8%) µg/mL following IV administration (Day 7). As expected, IV CBZ Cmax concentrations were elevated, 10.84 (CV=29.9%) µg/mL, compared to oral CBZ Cmax concentrations, 9.27 (CV=30.5%) µg/mL. However, elevated Cmax concentrations were transient in nature. CBZ AUCs (0-24 hrs) were also similar following oral administration, 193.3 (CV=29.7%) µg●h/mL, compared to IV administration, 178.13 (CV=25.1%) µg●h/mL . Finally, CBZ-10, 11-epoxide concentrations were slightly lower following IV dosing compared to oral dosing; suggesting a lack of 1st-pass metabolism following IV CBZ administration. As study enrollment is still ongoing, updated results, including those following a 5 minute infusion of CBZ, will be presented at the meeting. Conclusions: These preliminary data suggest that, on average, IV CBZ administered at a 70% dose conversion from patients’ oral dose and at a Q6h dosing interval, allowed patients to maintain total exposures to CBZ, as demonstrated by comparable IV and oral CBZ AUC and Cmin PK parameters, while tolerating an expected transient rise in CBZ Cmax concentrations.