Abstracts

Rationale: Once-daily extended-release (ER) AEDs offer potential adherence and tolerability advantages to b.i.d./t.i.d. immediate-release (IR) AEDs. However, clinicians may be hesitant to switch patients with refractory epilepsy to once-daily ER AEDs on the perception that failure to maintain a consistent dosing regimen poses a greater risk when the total daily dosage is administered as a once-daily vs. b.i.d. dose. 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. SPN-538 is bioequivalent to b.i.d. Topamax (TPM-IR, Janssen Pharmaceuticals). PK consequences of delayed, missed, and doubled doses of these agents were compared with computer simulation.Methods: A population PK model based on TPM plasma concentrations from PK studies (eg, study in epilepsy patients on stable maintenance dosages of b.i.d. TPM-IR switched to identical once-daily SPN-538 dosage) was used for comparative simulations of plasma concentration-time profiles if dosing was delayed 4-24 hrs; a single dose was missed; or a dose was accidentally doubled. Simulations also compared dosing nonadherence in adjunctive therapy with enzyme-inducing AEDs (EIAEDs) vs. monotherapy/neutral cotherapy (noninduced).Results: Simulated steady-state TPM concentrations during adherent dosing showed that peak-to-trough fluctuation was smaller and the profile flatter with once-daily SPN-538 than with b.i.d. TPM-IR. Delayed TPM-IR dosing (4-hr to 24-hr delay) produced greater decreases in trough (C_min) levels (9% to 31%) than delayed SPN-538 dosing (6% to 27%) in noninduced patients. A single missed dose reduced SPN-538 C_min by 27% and TPM-IR C_min by 21%. Accidental doubling of a dose increased SPN 538 C_max by 28% and TPM-IR C_max by 26%. In the presence of EIAEDs, similar trends were noted.Conclusions: Computer simulations showed that, due to slower and more prolonged TPM absorption from SPN-538, a delayed SPN-538 dose had less effect on TPM levels than a delayed b.i.d. dose of TPM-IR. The reduction in trough TPM levels after a missed SPN-538 dose (100% of total daily dosage) was only slightly greater than the C_min reduction after a missed TPM-IR dose (50% of total daily dosage). Simulation also showed that C_max increases following an accidentally doubled dose of SPN-538 or TPM-IR were comparable. The impact of a delayed, missed, or doubled dose on steady-state TPM concentration was consistently greater in the presence of EIAEDs. Based on these concentration-time profiles simulated at the same total daily dose, dosing irregularities with once-daily SPN-538 should pose no greater risk than irregularities with b.i.d. TPM-IR. After a missed dose, TPM levels can be restored by doubling the next SPN-538 dose, although the dose can be made up at any time. SPN-538 offers the convenience of once-daily TPM dosing without increasing the clinical risk of missing, delaying, or doubling a dose.