Abstracts

Rationale: Carbamazepine (CBZ) is a widely prescribed, oral antiepileptic drug approved in the United States and other countries. However, many patients are, on occasion, unable to take CBZ by mouth because of illness, injury, surgery, or changes in mental status. A new intravenous (IV) formulation (solubilized in a cyclodextrin matrix) is in clinical development, and a multicenter, sequential, open-label, Phase I study was conducted to assess the safety, tolerability, and comparative pharmacokinetics (PK) of IV and oral CBZ . Methods: Adult patients with epilepsy stabilized on a fixed oral dosage of CBZ (400-2,000 mg/day) were converted to IV therapy, based on an estimated 70% mean bioavailability of oral CBZ. At the conclusion of a 28-day, outpatient lead-in period, patients arrived at a research unit on Day -1 already on oral CBZ maintenance therapy. The following day (Day 0), patients continued on oral therapy and had serial blood sampling to determine the area under the concentration-time curve (AUC) for CBZ and CBZ-10,11-epoxide (CBZ-E), the active metabolite, over 12 hours. IV CBZ infusions were then administered over 15 or 30 minutes every 6 hours for 7 consecutive days (Days 1-7). A group of patients also received four 2-5 minute infusions on Day 8 (following the 7 days of 15-minute infusions). On Days 1, 7, and 8, extensive blood sampling was conducted during the first 6-hour IV CBZ dosing interval, for measurements of plasma CBZ and CBZ-E concentrations. Safety assessments were conducted through Day 38. Results: A total of 98 patients enrolled in the study. The mean daily oral CBZ dosage for 64 PK-evaluable patients with normal renal function was 962.5 mg, and the mean daily IV dosage was 675.1 mg (70% of the total daily oral dosage). PK data from these patients showed IV CBZ infused over 15 or 30 minutes or via 2-5 minute infusions led to C_min concentrations and overall exposure (AUC_0-24) of CBZ at steady state that were similar to those observed following oral CBZ at steady state (table). The 90% confidence intervals for the IV to oral CBZ ratios of geometric least-squares means (LSMs) for AUC_0-24, C_max, and C_min are also presented. For plasma CBZ, IV CBZ infused over 30 minutes was bioequivalent to oral CBZ, as the 90% CIs for the ratios of the LSMs for AUC_0-24, C_max, and C_min were within the 80% to 125% range. For the 15-minute and 2-5 minute infusions, the 90% CI ratios of the LSMs for AUC_0-24 and C_min were also within the 80% to 125% range. However, the 90% CI ratio of the LSM for C_max was greater than the upper limit of the 80% to 125% range. Conclusions: IV carbamazepine infused over 30 minutes every 6 hours is bioequivalent to oral carbamazepine. Thirty-minute CBZ infusions given every 6 hours at a 70% dosage conversion from patients oral dosages permitted patients to maintain their total CBZ exposures, as demonstrated by comparable IV and oral CBZ AUC and C_min parameters. C_max concentrations following 15-minute and 2-5 minute infusions transiently exceeded bioequivalence limits.