Abstracts

Rationale: An intravenous (IV) formulation of carbamazepine (CBZ), an antiepileptic drug (AED) solubilized in sulfobutylether ߭cyclodextrin (SBECD) sodium salt, has been developed for use in patients (pts) with epilepsy when oral administration is temporarily not feasible. The IV formulation (supplied as 10 mg/mL CBZ and 250 mg/mL SBECD) is well tolerated and bioequivalent to oral CBZ when infused at 70% of the total daily dose (TDD) every 6 hours (q6h). Herein, we report the pharmacokinetics (PK) of oral CBZ are compared to those of IV CBZ in pts with normal renal function (RF; creatinine clearance [CLCR] ?-90 mL/min), mild renal impairment (RI; CLCR=60?"89 mL/min), (RI), and moderate RI (CLCR=30?"59 mL/min). Methods: OV-1015 was a phase 1, open-label study in which adult pts with epilepsy who were receiving a stable oral CBZ dosage (400?"2,000 mg/day) were converted to IV CBZ infused at 70% of the oral TDD. The trial comprised three parts: 28-day outpatient lead-in period, 10-day inpatient period, and 30-day follow-up period. IV CBZ was administered as 15- or 30-min infusions q6h on Days 1?"7, and 2- to 5-min infusions on Day 8 for a subset of 15-min infusion pts. Serial blood samples were obtained on Day 1 (oral CBZ) and Day 7 (IV CBZ) of the inpatient period for pts receiving 15- and 30-min infusions, and on Day 8 for the pts who received 2- to 5-minute infusions. PK parameters of oral and IV CBZ were estimated through non-compartmental analysis using infusion duration and pt renal function. Patient CLCR was calculated by the Cockroft-Gault equation. Results: The population included 55 pts with normal RF (15-min: 34 pts; 30-min: 21 pts), 20 pts with mild RI (15-min: 10 pts; 30-min: 10 pts), and 2 pts with moderate RI (15-min: 1 pt; 30-min: 1 pt) who had evaluable PK data; 10 pts received 2- to 5-min infusions, 7 with normal RF and 3 with mild RI. Patient CBZ PK data by infusion duration and renal function status are summarized in Table 1. AUC0?"24 did not change based on pt RF for IV and oral CBZ. Apparent clearance (CL/F) decreased for pts with mild RI receiving 15- or 30-min infusions by only 5.71% and 3.01%, respectively, vs pts with normal RF (not significant). Similar analyses could not be done for pts with moderate RI since there were only 2 patients in this group. Conclusions: Mild RI did not have any clinically meaningful effect on oral or IV CBZ PK. The effects of moderate and severe RI (CLCR 30?"59 mL/min and 15?"29 mL/min, respectively) on CBZ PK are not known. Funding: Funding: Lundbeck LLC