Abstracts

Rationale: 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. Given the well-established clinical profile of immediate-release TPM (TPM-IR) >20 double-blind, randomized controlled trials in patients with epilepsy and a safety profile based on >4 million patient exposures SPN-538 has been approved on the basis of a bridging program that demonstrated PK bioequivalence of once-daily SPN-538 to twice-daily TPM-IR. The PK studies described here were conducted to demonstrate the equivalence of SPN-538 at multiple dose strengths as well as dose linearity.Methods: Two randomized, open-label, 4-treatment crossover studies were conducted in fasting healthy adults. Dose Strength Equivalence: A single 200-mg oral dose of SPN-538 administered as one 200-mg, two 100-mg, four 50-mg, and eight 25-mg capsules in random sequences. Dose Linearity: Four strengths of SPN-538 administered as a single 25-, 50-, 100-, and 200-mg capsule. Both studies included a 28-day screening period followed by four treatment periods, each separated by a 28-day washout. PK samples were obtained pre-dose and at specified time points through 168 hrs post-dose. PK analysis included all subjects who completed 2 treatment periods; safety evaluations included all who received 1 dose of study drug.Results: Dose Strength Equivalence. Safety population, n=34; PK analysis, n=26. All four 200-mg doses of SPN-538 (administered as 1, 2, 4, or 8 capsules) were bioequivalent based on 90% CIs for ratios (AUC_0-t, AUC_inf, and C_max) falling within the 80%-125% bioequivalence. Dose Linearity. Safety population; n=36; PK analysis, n=33. Dose-normalized ratios for AUC_0-t and AUC_inf 25 200 mg for all treatment comparisons demonstrated dose linearity, ie, 90% CIs for ratios were within 80%-125% limits. C_max exhibited linearity across all doses except for 25 mg, which exhibited disproportionately lower C_max. In the safety analyses, SPN-538 was well tolerated; most AEs were mild to moderate. No unexpected tolerability/safety signals were observed.Conclusions: Dose Strength Equivalence. SPN-538 exposure was bioequivalent whether a 200-mg oral dose was administered as 25-, 50-, 100-, and 200-mg capsules. Dose Linearity. PK of SPN 538 are linear across 50 200 mg dosage range. At 25 mg, PK is nonlinear possibly due to TPM binding to carbonic anhydrase in red blood cells. Studies funded by Supernus Pharmaceuticals, Inc.