Abstracts

Rationale: Licarbazepine (10,11-dihydro-10-hydroxy-5H-dibenz-[b,f]azepine-5-carboxamide) ?" also known as MHD (10-monohydroxy derivative) ?" is a potent sodium channel blocker comprised of two equally active enantiomers (S-licarbazepine [S-MHD], also known as eslicarbazepine [ESL]; R-licarbazepine [R-MHD]). Oxcarbazepine immediate-release (OXC-IR) administered BID was the initial means of achieving therapeutic LCBZ concentrations. Clinical usefulness of OXC-IR was often limited by tolerability issues due to CNS toxicity at peak MHD (ie, LCBZ) concentrations. Approaches to achieving therapeutic LCBZ levels using QD dosing have since become available, including an extended-release (XR) formulation of OXC (Oxtellar XR?(R), Supernus Pharmaceuticals, Inc.) and an IR formulation of eslicarbazepine acetate (ESL-Ac). We report results of a study characterizing the pharmacokinetic profile of Oxtellar XR, which was specifically designed to produce relatively constant steady-state LCBZ plasma concentrations with QD dosing. Methods: Single-center, open-label study in healthy adult volunteers. Oxtellar XR was titrated to 1200 mg Q24h over 7 days; maintenance period was 7 days. At end of maintenance, serial blood samples for measuring LCBZ and OXC concentrations were collected pre-dose (0) and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 18, 24, 36, 48, 60, and 72 hrs post-dose. Steady-state PK parameters of interest: AUC0-24, Tmax, Cmax, Cmin, % fluctuation ([Cmax-Cmin]/Cavg x100). LCBZ concentrations were determined with a non-chiral method. Results: Pharmacokinetic Analysis population, N=28. Median AUC0-24 (g?-?h/mL): LCBZ, 368; OXC, 10. Median Tmax: LCBZ, 7 hr; OXC, 5 hr. Median Cmax (g/mL): LCBZ, 18.1; OXC, 0.9. Median Cmin (g/mL): LCBZ, 11.8; OXC, 0.2. Median LCBZ fluctuation, 40%. Peak-trough concentration ratio: 1.5. Figure shows steady-state LCBZ plasma concentration-time profile. Conclusions: LCBZ (combined S- and R-licarbazepine) accounted for ~97% of biologically active drug in plasma following Oxtellar XR administration. The plasma concentration-time profile was relatively flat over 24-hr dosing interval. An indirect comparison of data from healthy volunteers suggests that LCBZ Cmax was ~25% lower with 1200 mg QD Oxtellar XR vs. 1200 mg QD ESL-Ac. Percent fluctuation from the average LCBZ concentration and peak-trough ratio were substantially less with QD Oxtellar XR vs. QD ESL-Ac (Oxtellar XR: 40% and 1.5, respectively; ESL-Ac: 113% and 2.9) while 24-hr LCBZ exposures appeared to be similar. Differences in plasma concentration-time profiles for the two drugs were consistent with characteristics of XR vs. IR formulations. QD Oxtellar XR, with its lower peak concentrations and more constant LCBZ plasma concentrations over a 24-hr dosing interval, may reduce the risk of LCBZ concentration-related CNS toxicity relative to IR formulations of LCBZ prodrugs. Funding: Study funded by Supernus Pharmaceuticals, Inc.