Pharmacokinetic simulations of topiramate plasma concentrations following dosing irregularities with extended-release vs. immediate-release formulations

Background: Once-daily extended-release (XR) antiepileptic drugs (AEDs) offer potential adherence and tolerability advantages over their BID immediate-release (IR) counterparts. However, patients with epilepsy will inevitably be at least occasionally nonadherent with a prescribed dosing regimen, regardless of formulation. Although perturbations in plasma concentrations due to dosing irregularities may have clinical consequences for AEDs with concentration-response relationships, clinical studies that deliberately expose patients to specific dosing irregularities in order to assess the effect on plasma concentrations and determine appropriate corrective actions would be unethical. Methods: Computer simulation was used to assess the impact of irregular dosing on topiramate (TPM) concentrations in noninduced (monotherapy/neutral cotherapy) and induced (adjunctive therapy with enzyme-inducing AEDs) states using a population pharmacokinetic (PK) model developed to predict steady-state plasma concentration-time profiles produced by once-daily Trokendi XR (R) (extended-release topiramate capsules, Supernus Pharmaceuticals) and BID TPM-IR. Results: Computer simulations predicted that, relative to adherent dosing, delaying a dose 4 to 24 h in noninduced patients would decrease trough (C-min) levels 9% to 31% in the case of TPM-IR and 6% to 27% with Trokendi XR; a single omitted dose would reduce C-min by 21% (TPM-IR) and 27% (Trokendi XR). After dose recovery to correct for a delayed or omitted dose, simulated peak concentration (C-max) was higher than steady-state C-max, regardless of formulation, although the magnitude of "overshoot" was consistently lower with Trokendi XR vs. TPM-IR. Doubling of a dose would increase C-max by 26% and 28%, respectively. Predicted changes for nonadherent vs. adherent dosing were greater in the induced vs. noninduced state but were generally comparable for the two TPM formulations. Because the long half-life of TPM has been cited as a justification for QD dosing of TPM-IR, simulations also compared steady-state PK profiles of once-daily Trokendi XR and QD TPM-IR. Predicted TPM plasma concentration-time profiles were markedly different, as demonstrated by peak-trough fluctuation (QD TPM-IR, 64%; QD Trokendi XR, 18%) and 34% lower C-min with QD TPM-IR. Conclusions: Based on these simulations, dosing irregularities with once-daily Trokendi XR should pose no greater risk than with BID TPM-IR. In the event of a delayed or omitted Trokendi XR dose, TPM concentrations can be restored in noninduced and induced states by administering the delayed/omitted dose at any time during the next dosing interval or by adding the missed dose to the next scheduled dose. (C) 2015 The Authors. Published by Elsevier Inc.