Abstracts

Rationale: Carbamazepine (CBZ) is an oral antiepileptic drug (AED) for the management of partial seizures. Although it is insoluble in water, an intravenous (IV) formulation has been developed in which CBZ is solubilized in sulfobutylether ߭cyclodextrin (SBECD) sodium salt (Captisol). IV CBZ (10 mg/mL CBZ and 250 mg/mL SBECD) is bioequivalent to oral CBZ when infused at 70% of the total daily dose (TDD) every 6 hours (q6h) and well tolerated. SBECD is eliminated unchanged by renal excretion. The half-life (t) of SBECD is increased in patients (pts) with moderate renal impairment (RI) compared to pts with normal renal function (RF; 8.9 and 1.8 h, respectively); mean AUC and Cmax have also been shown to be increased in this population. This analysis describes the pharmacokinetics (PK) of SBECD in pts with normal RF and mild RI who participated in study OV-1015 of IV CBZ. Methods: Phase 1 trial OV-1015 was open-label in design. Adult pts with epilepsy and normal RF (creatinine clearance [CLCR] ?-90 mL/min), mild RI (CLCR=60?"89 mL/min), or moderate RI (CLCR=30?"59 mL/min) receiving a stable oral CBZ dosage (400?"2,000 mg/day) were converted to IV CBZ (70% of the oral TDD). The trial comprised a 28-day outpatient lead-in period, an up to 10-day inpatient period, and a 30-day follow-up period. IV CBZ was administered over 15 or 30 min q6h on Days 1?"7 of the inpatient period. In this post hoc analysis, the PK of SBECD following single-dose (Day 1) and multiple-dose (Day 7) administration of the IV CBZ formulation, and the effect of infusion duration, were assessed. Results: The post hoc analysis included 35 pts with normal RF (30 min: 16 pts, 15 min: 19 pts), 16 pts with mild RI (30 min: 9 pts; 15 min: 7 pts), and 2 pts with moderate RI (30 min: 1 pt; 15 min: 1 pts). Mean pt age was 45.9 y (range: 20?"68 y) and 36% were male; the demographic makeup of each infusion group varied. PK data for 50 pts (normal RF and mild RI) were evaluable for Day 1, and 51 pts had complete or partial PK data for Day 7. On Day 1, SBECD exposures were similar for both infusion groups independent of renal function (mean AUC0?"8: 782?"906 gh/mL), but mean Cmax was notably greater in the 15-min groups (normal RF: 779 g/mL and mild RI: 725 g/mL vs 30-min normal RF: 520 g/mL and mild RI: 478 g/mL). On Day 7, steady-state SBECD exposures were similar in pts with normal RF (30 and 15 min) and mild RI (15 min) (mean AUCt: 830-1015 gh/mL). Steady-state mean Cmax was notably greater in the 15-min groups, but similar for pts with normal RF and mild RI with the same duration cohort. The mean ratios (%CV) of Captisol AUC on Days 1 and 7 were 1.128 (14%) and 1.062 (15%) for pts with normal RF and 1.141 (11%) and 1.114 (11%) for pts with mild RI (30 and 15 min, respectively). Conclusions: Steady-state SBECD PK was similar to single-dose PK following IV CBZ infusions (70% of oral TDD) of 30- and 15-min duration q6h, indicating linear PK. The accumulation of SBECD, a potentially nephrotoxic ingredient of IV CBZ, was comparable between pts with normal RF and mild RI after 7 days of IV CBZ treatment. SBECD is known to accumulate in patients with moderate to severe RI. Funding: Funding: Lundbeck LLC