Abstracts

Rationale: To achieve the potential tolerability and adherence advantages of extended-release (ER) AEDs, clinicians need practical dosing guidance for an IR-to-ER AED switch in epilepsy patients, particularly for patients receiving inducing AEDs. SPN-538 (Trokendi XR, Supernus Pharmaceuticals, Inc.) is a novel extended-release, once-daily capsule formulation of TPM that may improve tolerability and enhance adherence. Based on a study in healthy volunteers, once-daily SPN-538 is pharmacokinetically bioequivalent to the original TPM-IR, Topamax (Janssen Pharmaceuticals), on all standard PK parameters. In the bioequivalence study, the more consistent TPM concentration-time profile of SPN-538 was also associated with significantly less negative cognitive effects measured as verbal fluency. Our study compared TPM PK in epilepsy patients switched overnight from b.i.d. Topamax to an identical dosage of once-daily SPN-538. A sequential design was used to mimic clinical practice of an IR-to-ER AED switch.Methods: In this open-label study of adults with partial-onset or primary generalized seizures receiving TPM-IR, patients were treated with the same total daily TPM dose throughout the 14-day baseline (b.i.d. Topamax) and 14-day SPN-538 treatment phase. PK samples were drawn over 24-hr post-dose period at end of baseline and treatment phases for steady-state PK analysis. SPN-538/TPM-IR ratios for conventional PK criteria (AUC_0-24, C_max, C_min) normalized to 200-mg dose were determined. Samples were also drawn over the 24-hr period following first dose of SPN-538. In addition to seizure counts and safety data, assessments included patient preference surveys.Results: Key demographic/disease characteristics of the study population were: mean age, 40 yrs; 71% female; mean epilepsy duration, 20 yrs; median duration of TPM therapy, 9.5 months. At steady-state (PK Population, N=62), SPN-538/TPM-IR ratios for dose-normalized AUC_0-24, C_max, and C_min were 99%, 95%, and 97%, respectively (noninduced, n=49: 102%, 98%, and 103%; induced, n=13: 102%, 96%, and 90%). Mean dose-normalized C_avg was the same with b.i.d. TPM-IR and once-daily SPN-538 (5.8 g/mL); median fluctuation was less (34% vs 48%) and T_max was longer (5 hrs vs 1 hr) with SPN-538. PK profile of SPN-538 after first dose was consistent with profile at steady state. All AEs were mild to moderate. The only AEs reported by >1 patient were fatigue (n=2) and headache (n=4) occurring during SPN-538 treatment. The overnight switch to SPN-538 was not associated with deterioration in seizure control or new safety signals. In patient surveys, 93% preferred SPN 538 over TPM-IR; 92% believed that once-daily dosing would facilitate adherence.Conclusions: These results support an overnight mg-for-mg switch from TPM-IR to once-daily SPN-538 in patients with epilepsy, regardless of concomitant medications. Study funded by Supernus Pharmaceuticals, Inc.