Search

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® (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.

While antiepileptic drugs (AEDs) remain the primary treatment for epilepsy, many patients continue to have seizures. Uncontrolled seizures may be related to AED half-life, since short half-life (SHL) AEDs require more frequent dosing compared with the simplified regimens of long half-life (LHL) AEDs. Long half-life AEDs may also improve seizure control by extending missed dose forgiveness periods. The value of LHL AEDs may be assessed as reduced healthcare utilization. The study's objective was to examine the impact of adding an LHL versus SHL adjunctive AED on the risk of hospitalizations in patients with uncontrolled epilepsy.This was a retrospective, longitudinal cohort study using the Symphony Health Solution Patient Integrated Dataverse. Patients ≥12 years old with uncontrolled epilepsy (≥2 medical claims ≥30 days apart) were identified during a study period (8/1/2012-7/31/2017). Patients were selected if they were subsequently initiated an adjunctive AED (excluding modified release formulations), and the prescription date served as the index. Patients were stratified into two mutually exclusive cohorts based on the index AED half-life (≤20 versus20 h). Poisson regressions with robust error variances were performed for the relative risks (RRs) of all-cause, epilepsy-related, and injury-related hospitalizations.A total of 4984 patients were identified (2705 in the LHL and 2279 in the SHL cohort). Compared with those in the SHL cohort, patients in the LHL cohort were significantly younger [mean (SD, years): 43.9 (18.5) versus 49.2 (17.2), p 0.001] and were less comorbid [mean (SD) of Charlson comorbidity index: 1.2 (1.8) versus 1.8 (2.2), p 0.001]. In the one-year postindex date, adjusting for group differences, the risks of both all-cause and epilepsy-related hospitalizations were significantly lower in the LHL cohort than in the SHL cohort [all-cause: 0.84 (95% CI: 0.76-0.93), p = 0.0006; epilepsy-related: 0.83 (0.73-0.94), p = 0.0046].Injury-related hospitalizations did not differ between LHL and SHL cohorts.In patients with uncontrolled epilepsy who were initiated on an adjunctive AED, the choice of an LHL versus SHL was associated with significantly lower risks of all-cause and epilepsy-related hospitalizations.

“Forgiveness” – the difference between a drug's postdose duration of action and its prescribed dosing interval – estimates the margin of therapeutic effect following a missed dose. Because this margin presumably decreases as dosing becomes less frequent, QD dosing of an antiepileptic drug (AED) is expected to be less forgiving than more frequent (e.g., BID) dosing of that same AED. However, if the AED is reformulated as an extended-release (XR) preparation, drug input may be prolonged relative to its immediate-release (IR) counterpart. It therefore stands to reason that forgiveness could be increased by an XR AED that extends the period during which therapeutic plasma concentrations are maintained if a dose is missed. Computer simulation was used to estimate forgiveness for an IR formulation of a hypothetical AED and its XR counterparts reformulated for less frequent dosing. Simulations determined forgiveness when the hypothetical IR AED was dosed TID, BID, and QD and when suitably designed XR formulations were dosed BID and QD. Simulations showed that forgiveness for an XR formulation can equal or exceed that for an IR formulation dosed more frequently.

Predictors and consequences of inadequate compliance with seizure medications were assessed using a 10-item postal survey. Dose omissions were reported by 71% of the 661 respondents (2 � 2 doses of seizure medications), with 45% of patients reporting a seizure after a missed dose, at some time during treatment. Dose omission was more likely with longer use of seizure medications (more than 5 years, P < 0:01). Having seizures after missed doses was associated with number of seizure medication doses (P ¼ 0:04) and number of seizure medication tablets/capsules (P ¼ 0:01). Odds ratios showed that each increase in dose frequency (one, two, three, or four doses daily) increased the likelihood of a seizure after a missed dose by 36%. Taking larger numbers of tablets/capsules increased the odds of having a seizure after missed doses by 43%. These data provide evidence that medication compliance remains an important issue in epilepsy treatment. 2002 Elsevier Science (USA). All rights reserved.