Abstracts

Rationale: Dose-management strategies (slow titration, low doses) improve the tolerability of TPM, a potent, broad-spectrum AED that can cause distinctive cognitive symptoms (eg, word-finding difficulty). Neuropsychometric tests have shown significant negative changes, especially in verbal fluency, in a relatively small subset of patients receiving TPM-IR. SPN-538 (Trokendi XR, Supernus Pharmaceuticals, Inc.) is a novel extended-release, once-daily capsule formulation of TPM that may improve tolerability and adherence. In a crossover study in healthy volunteers establishing bioequivalence of once-daily SPN-538 to b.i.d. TPM-IR (200 mg/day), effects of treatments on cognitive function were compared.Methods: Design: Single-blind, randomized-sequence, crossover study in healthy adults. Treatments: b.i.d. TPM-IR and once-daily SPN-538 (AM, active drug; PM, matching placebo) force-titrated in 50-mg weekly increments over 4 wks to 200 mg/day for 10 days; 32-day washout between periods. Cognitive tests (verbal fluency: Controlled Oral Word Association, COWA; processing speed: Digit Symbol Substitution Test, DSST) performed before the AM dose on Days 1 (baseline); 8 (50 mg/day), 15 (100 mg/day), 22 (150 mg/day), 31 (200 mg/day), and 38 (washout). Between-treatment comparisons were evaluated by fitting a repeated measures linear mixed model with fixed effects for treatment, sequence, period, day, and treatment by day.Results: In the per-protocol analysis of all subjects with data (TPM-IR, n=39; SPN-538, n=34), COWA change scores favored once-daily SPN-538 over b.i.d. TPM-IR at all test points; differences were significant at 50 (P=0.05) and 100 mg/day (P=0.0002) and for the entire treatment period (P=0.005). Subjects with moderate/severe (>1 SD) negative COWA changes: TPM-IR, 42%; SPN-538, 12%). Similar patterns for DSST changes did not reach statistical significance.Conclusions: Based on the per-protocol analysis of COWA change scores, the concentration-time profile of once-daily SPN-538 was associated with significantly less negative impact on COWA despite PK bioequivalence to b.i.d. TPM-IR on all standard PK parameters, similar C_avg0-24 (SPN-538, 6.1 g/mL; TPM-IR, 6.3 g/mL), and nearly identical mean TPM concentrations (5.6 g/mL) when cognitive function tests were performed 18 (SPN-538) and 10 (TPM-IR) hrs after T_max. Once-daily SPN-538 produces more consistent TPM plasma concentrations (14% difference, P<0.001, in peak-trough fluctuation) due to a markedly slower absorption rate (24-fold difference vs TPM-IR). COWA, known to be highly sensitive to specific effects of TPM, may be sensitive to differences in rates at which TPM concentrations increase/change. Further work to confirm these findings as well as elucidate their potential clinical significance is warranted. Funded by Supernus Pharmaceuticals, Inc.