Abstracts

Rationale: The oral antiepileptic drug (AED) carbamazepine (CBZ) is typically used for the long-term management of partial seizures. A solubilized formulation of CBZ (sulfobutylether ߭cyclodextrin [SBECD] sodium salt, Captisol?(R)) can ensure uninterrupted CBZ administration in patients requiring intravenous (IV) AED administration (eg, surgery). Bioequivalence of IV CBZ (10 mg/mL CBZ and 250 mg/mL SBECD) and oral CBZ when infused at 70% of the individual's total daily dose (TDD) in divided doses administered every 6 hours (q6h) was demonstrated in study OV-1015, with similar safety profiles between formulations. In accordance with regulatory guidance, a QT analysis was conducted as part of study OV-1015; the results are summarized herein. Methods: In the open-label, phase 1 trial OV-1015, adult participants with epilepsy receiving a stable oral CBZ dosage (400 to 2,000 mg/day) were enrolled. Participants were switched to IV CBZ infused at 70% of the oral TDD. The trial comprised a 28-day outpatient period, an inpatient period (up to 10 days), and a 30-day follow-up period. IV CBZ was administered as 15- or 30-min infusions q6h on Days 1?"7. A subset of participants in the 15-min infusion group received rapid (2- to 5-min) infusions on Day 8. No drug-free baseline ECGs were available because participants were receiving a stable dosage of CBZ. Triplicate pre-dose digital ECGs were extracted from a 12-lead Holter at 30 min, 15 min, and 5 min on Days 0, 1, and 7, as well as Day 8 for participants receiving rapid infusions. The primary ECG endpoint was QTc calculated using Fridericia's equation (QTcF). All participants who received ?-1 dose of IV CBZ and had ?-1 post-infusion ECG with a corresponding plasma concentration were included in the safety analysis set for ECG analysis. Results: Of the 98 participants who received IV CBZ in this study, 97 were included in this QT analysis; one participant was unsuitable for QT analysis because their ECGs showed complete right bundle branch block (QRS>120 msec). QTc intervals were similar for participants across all infusion duration groups, and there were no instances a QTcF value exceeding 500 msec. The QTc interval appeared to decrease by 0.577 msec/(ng/mL) with increasing plasma concentrations of CBZ (oral and IV). The overall incidence of QTc values exceeding 450 msec was < 2%. Overall, QTc intervals were longer pre-dose than post-dose for both oral and IV CBZ formulations. Conclusions: QTc intervals following administration of CBZ did not differ by formulation (oral or IV) or by IV CBZ infusion duration. A concentration-effect analyses indicated QTc decreased with increasing CBZ plasma concentrations. Funding: Funding: Lundbeck LLC