Abstracts

Rationale: SPN-538 (Trokendi XR^®; Supernus Pharmaceuticals, Inc.) is a novel extended-release, once-daily capsule formulation of topiramate (TPM). In healthy volunteers, once-daily 200 mg SPN-538 was bioequivalent to 100 mg BID immediate-release TPM (TPM-IR; Topamax^®, Janssen Pharmaceuticals). Slower drug absorption with SPN-538 was associated with significantly less negative impact on verbal fluency in this study. To better characterize the pharmacokinetic (PK) profiles of TPM formulations when used clinically, PK data from epilepsy patients participating in a conversion study were analyzed using a population PK approach. Methods: A linear 2-compartment model developed previously from a single-dose study in healthy adults was applied to PK data from a conversion study in which adults with epilepsy on stable doses of TPM-IR BID were switched to the same total daily dose of once-daily SPN-538 for 14 days. Data analysis: nonlinear mixed-effects modeling (NONMEM). Absorption parameters: absorption rate constant (k_a, representing drug release and uptake), absorption lag, and relative bioavailability. Systemic parameters: apparent clearance (CL/F), apparent volume of central compartment (V₁/F), apparent distributional clearance (CL₂/F), and apparent volume of peripheral compartment (V₂/F). Covariates investigated: body size, age, gender, race, organ function (within normal limits), TPM daily dose, and concomitant AEDs. Model goodness of fit was evaluated using the objective function (-2 x log likelihood) and graphical error analysis. Final model was validated using a bootstrap analysis. Results: Final NONMEM dataset: TPM plasma concentration vs time data for 62 epilepsy patients (median number of PK data points per patient, n=47). Daily dose distribution at study entry: 200 mg, n=27; 250 or 300 mg, n=12; 400 mg, n=23. The final model, which included covariates for weight and concomitant use of enzyme-inducing AEDs (EIAEDs), fit observed patient data well. Absorption rate for TPM-IR morning dose (TPM-IR_am k_a=2.25/hr) was faster than for the evening dose (k_a=0.396/hr); SPN-538 absorption was 25X slower (k_a=0.092/hr) than TPM-IR_am. Analysis indicated that TPM exposure may vary inversely with weight and that concomitant EIAEDs increased TPM clearance, typically by a factor of 1.75. Age, gender, race, organ function (within normal limits), and TPM daily dose had no effect on TPM clearance. Typical value for CL/F was 1.3 L/hr (20% between-subject variability). Conclusions: In a population PK model developed and validated for TPM administered as TPM-IR BID and once-daily Trokendi XR^® (SPN-538) in patients with epilepsy, absorption rate from Trokendi XR was ~25X slower than TPM-IR_am. Results confirm and further explain observations in healthy adults that once-daily Trokendi XR produces more constant plasma concentrations over a 24-hour dosing interval vs TPM-IR BID. Study sponsor: Supernus Pharmaceuticals, Inc.