Population Pharmacokinetic Evaluation and Missed‐Dose Simulations for Eslicarbazepine Acetate Monotherapy in Patients With Partial‐Onset Seizures

Abstract

Given the potential consequences of antiepileptic therapy nonadherence, missed-dose scenarios of 12- to 48-hour dose delays (4-hour intervals) for eslicarbazepine acetate monotherapy were evaluated using simulated plasma concentrations of a population pharmacokinetic model (representing 493 subjects). When 1600-mg doses were delayed 12 to <16 or 36 to <44 hours, simulations showed immediate administration of 1600 mg followed by the same dose at the scheduled time maintained plasma concentrations within the target concentration range. With 16- to 24- or 44- to 48-hour delays, administration of 2400 mg at the scheduled time followed by resumption of 1600 mg/day maintained plasma concentrations within the target concentration range. For exploratory purposes, the population pharmacokinetic model was refined to predict (n = 6 subjects) and also to allow for simulation of cerebrospinal fluid concentrations. Based on the plasma concentration simulations conducted herein, potential dosing recommendations were developed that suggest a missed ESL dose should be taken when remembered, and the usual dose regimen resumed. If it is remembered within 4 hours of the next dose, 1.5 times the usual dose should be taken immediately, the scheduled dose for that day should be skipped, and the usual regimen resumed the next day.

What should patients do if they miss a dose? A systematic review of patient information leaflets and summaries of product characteristics

“…Similar studies have been performed with antihypertensive drugs [22][23][24][25][26][27][28][29][30] which indicate, for instance, amlodipine to be more forgiving than either enalapril or diltiazem, and to be more forgiving when combined with olmesartan than with perindopril [31]. For warfarin, pharmacokineticpharmacodynamic models have been proposed to inform labelling recommendations [32], and population pharmacokinetic models have been used to simulate missed doses of [33]. Pharmacometric analyses have also been used for a range of psychoactive treatments [34], and ought to be performed routinely to provide evidence for PIL and SmPC instructions on missed doses; especially for less forgiving treatments.…”

Handling Delayed or Missed Dose of Antiseizure Medications

“…21 However, because the prediction and simulation by the gold-standard population PK software (NONMEM) used in previous studies is too time consuming, only typical patients with commonly used regimens were investigated. [16][17][18][19]21 Optimal remedial regimens for various delayed or missed dose scenarios were incompletely explored.…”

Designing drug regimens that mitigate nonadherence

“…The model in the present work generalizes our previous model in [20] which took the drug absorption rate to be infinite. Many groups have used numerical simulations of computational models to study medication nonadherence [31,32,[42][43][44][45][46][47][48][49][50][51][52]. Our results are in general agreement with some of the conclusions of this prior computational work which investigated some specific drugs, including (i) the efficacy of a double dose following a missed dose and (ii) that adherence thresholds should depend on specifics of the drug regimen.…”

“…model cannot predict how adherence might increase by switching from an IR to an XR regimen, our model can predict the value of p XR needed so that ε XR = ε IR for a given value of p IR . In the right panel of Figure 7, we plot this value of p XR as a function of p IR , where the dosing intervals are as in (50) and the drugs are lamotrigine (k e = 0.03 hr −1 , k IR a = 3 hr −1 , k XR a = 0.07 hr −1 [31]), a hypothetical antiepileptic drug (AED) considered in [33] (k e = 0.08 hr −1 , k IR a = 5 hr −1 , k XR a = 0.5 hr −1 ), and Quetiapine fumarate (k e = 0.12 hr −1 , k IR a = 1.46 hr −1 , k XR a = 0.1 hr −1 [32]). This plot shows that, for lamotrigine, p XR is only slightly larger than p IR for most values of p IR , and p XR is actually less than p IR for large values of p IR .…”