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. 2023 Feb 28;100(9):e921–e931. doi: 10.1212/WNL.0000000000201604

Handling Delayed or Missed Dose of Antiseizure Medications

A Model-Informed Individual Remedial Dosing

Zi-ran Li 1,✉, Chen-yu Wang 1, Wei-wei Lin 1,✉, Yue-ting Chen 1, Xiao-qin Liu 1, Zheng Jiao 1,✉
PMCID: PMC9990430  PMID: 36450606

Abstract

Background and Objectives

Delayed or missed antiseizure medications (ASMs) doses are common during long-term or lifelong antiepilepsy treatment. This study aims to explore optimal individualized remedial dosing regimens for delayed or missed doses of 11 commonly used ASMs.

Methods

To explore remedial dosing regimens, Monte Carlo simulation was used based on previously identified and published population pharmacokinetic models. Six remedial strategies for delayed or missed doses were investigated. The deviation time outside the individual therapeutic range was used to evaluate each remedial regimen. The influences of patients' demographics, concomitant medication, and scheduled dosing intervals on remedial regimens were assessed. RxODE and Shiny in R were used to perform Monte Carlo simulation and recommend individual remedial regimens.

Results

The recommended remedial regimens were highly correlated with delayed time, scheduled dosing interval, and half-life of the ASM. Moreover, the optimal remedial regimens for pediatric and adult patients were different. The renal function, along with concomitant medication that affects the clearance of the ASM, may also influence the remedial regimens. A web-based dashboard was developed to provide individualized remedial regimens for the delayed or missed dose, and a user-defined module with all parameters that could be defined flexibly by the user was also built.

Discussion

Monte Carlo simulation based on population pharmacokinetic models may provide a rational approach to propose remedial regimens for delayed or missed doses of ASMs in pediatric and adult patients with epilepsy.

Epilepsy is a chronic disorder of the brain and affects around 50 million people worldwide.1 Roughly half of the patients with epilepsy have coexisting physical or psychiatric comorbidities, and the overall mortality rate is increased by 2- to 3-fold compared with the general population.2 Antiseizure medications (ASMs) are the initial treatment modality for most patients with epilepsy.3 With the appropriate use of ASMs, up to 70% of patients could become seizure-free.4

Because patients with epilepsy often require long-term or lifelong ASM treatment, poor medication adherence becomes a major problem.5 The nonadherence was reported in approximately 30%–50% of patients with epilepsy.6,7 Among all patterns of nonadherence, missed doses were reported by 71% of responsive patients.8 Because nonadherence has been associated with poor seizure control, increased time of hospitalization, and increased morbidity,9 handling a delayed or missed dose becomes a common concern for the patients and health care providers.10

Package inserts of most ASMs, such as valproic acid (Depakote) and levetiracetam (Keppra), approved by the US Food and Drug Administration (FDA) recommend that “If a dose is missed, it should be taken as soon as possible unless it is near the next scheduled dose. If a dose is skipped, the patient should not double the next dose.”11,12 A patient information leaflet approved by Medicines and Healthcare Products Regulatory Agency of the United Kingdom and the European Medicines Agency along with Medicines and Medical Devices Safety Authority in New Zealand proposed similar recommendations.13,14 However, no convincing evidence was provided for those recommendations, and the appropriate remedial dosing regimens for delayed or missed doses remain unclear.

Too large a remedial dose may result in concentration-dependent adverse drug reactions such as dizziness, nausea, and emesis, whereas inadequate remedial dose may increase the risk of seizure recurrence.3 Therefore, optimal remedial dosing instructions for the delayed or missed dose of ASMs are imperative.15

To address a delayed or missed dose, considerable effort and time are required to explore and evaluate remedial strategies. Population pharmacokinetic (PK) modeling and simulation are regarded to be efficient and have been applied to develop remedial dosing regimens for ASMs, including carbamazepine,16 valproic acid,17 lamotrigine,18 eslicarbazepine acetate,19 levetiracetam,20 and phenobarbital.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.16-19,21 Optimal remedial regimens for various delayed or missed dose scenarios were incompletely explored.

Therefore, this study aims to comprehensively provide individual remedial dosing regimens for patients with epilepsy who had a delayed or a missed dose of 1 of the 11 commonly used ASMs using a fast algorithm of RxODE in R. Moreover, the influence of patients' demographics, concomitant medication, and dosing intervals on remedial regimens was investigated.

Methods

Rationale

During successful ASM treatment, the drug concentration fluctuates within the therapeutic range for patients with full adherence. However, if the patient delayed or missed a dose, the drug concentration would deviate from the patient's therapeutic range. Therefore, remedial dosing aims to restore the drug concentration to the patient's therapeutic range and reduce the time outside the patient's therapeutic range as much as possible.

As the therapeutic window can vary significantly from patient to patient, guidelines for therapeutic drug monitoring of ASMs recommend using the individual therapeutic range of the patient instead of the fixed reference range.22 In our study, the patient with full adherence is assumed to obtain desired efficacy and safety. Therefore, the range between the 5th percentile trough concentration and the 95th percentile peak concentration at the steady state of a given dose is set as the patient's individual therapeutic range.16-18

To evaluate the impact of nonadherence and remedial regimens, the total deviation time where concentrations are outside the individual therapeutic range was estimated. It was calculated by the sum of the deviation time above and below the individual therapeutic range. The schematic diagram of the rationale for remedial dosing regimen selection is presented in Figure 1. The remedial regimens with a less total deviation time were regarded to be more appropriate.17,18,23

Figure 1. Schematic Diagram of Remedial Dosing Regimens.

Figure 1

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Concentration-time curves: (a) under full adherence and (b) taking the regular dose when delayed by 7 hours; patients were assumed to take multiple doses and reach a steady state. The dashed lines represent the individual therapeutic range. The bold black lines represent the deviation time outside the individual therapeutic range. A round tablet represents a regular dose, and a dashed round tablet represents a missed dose. The red line represents the median of simulated concentration-time curves. The pink shadows represent the distribution of the range between the 5th and 95th percentile of the simulated concentration. The light pink shadows on the right represent the distribution of the simulated concentration-time curves.

Remedial Dosing Regimen

Population PK Characteristics of ASMs

A total of 11 commonly used ASMs were included in this study: carbamazepine, clobazam, eslicarbazepine acetate, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid, and zonisamide. Population PK studies of these ASMs were retrieved from published reviews or identified in the PubMed and Embase databases. Identification was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.24 The details for study identification are described in eAppendix 1, eTable 1, eAppendix 2, and eFigure 1 (links.lww.com/WNL/C511).

The population PK model and the corresponding fixed-effect parameter estimates for simulation were set as the values in each of the previous studies. Regarding the random effects, between-subject variability was set as the reported values, and the residual unexplained variability of all models was set as an additive error of 0.1 mg/L or a proportional error of 1% to facilitate the Monte Carlo simulation.25 The simulations were performed using RxODE (version 0.9.1–8)26 in R (version 3.6.1).

Remedial Dosing Regimen Design

For the clinical feasibility, when a dose is delayed or missed, the patients are recommended to take the remedial dosing regimen at 2 time points, including the time when they remembered the delayed dose and the time for the next scheduled dose.10,27 Therefore, 6 remedial strategies were investigated. The graphic remedial strategies are shown in Figure 2, and details are listed below:

  • Strategy A: skip the delayed dose, and resume the regular dosing regimen at the next scheduled dosing time;

  • Strategy B: take the delayed dose immediately, and resume the regular dosing regimen at the next scheduled dosing time;

  • Strategy C: take the remedial dose immediately, and then resume the regular dosing regimen at the next scheduled dosing time;

  • Strategy D: take the delayed dose immediately, followed by a remedial dose at the next scheduled dosing time, and then resume the regular dosing regimen;

  • Strategy E: take both the remedial dose and the delayed dose immediately, skip the next scheduled dose, and then resume the regular dosing regimen;

  • Strategy F: do not take the remedial dose immediately but take both the remedial dose and the delayed dose at the next scheduled dosing time, and then resume the regular dosing regimen.

Figure 2. Graphical Representation of 6 Remedial Strategies Following a Delayed or Missed Dose.

Figure 2

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A round tablet represents a regular dose, and a half-round tablet represents half of the regular dose. The n represents the delayed time.

Impact of Patients' Demographics, Concomitant Medication, and Scheduled Dosing Interval

To explore the impact of patients' demographics on remedial regimens, pediatric patients (10 years old, 30 kg, and 140 cm) and adult patients (40 years old, 70 kg, and 180 cm) taking tablets were employed as typical patients. Moreover, for patients taking syrup or oral solution, younger children (5 years old, 16 kg, and 110 cm) were employed as typical patients. The demographic characteristics of virtual patients and the corresponding dosing regimens are summarized in Table 1.

Table 1.

Demographic Characteristics of Simulated Patients and Corresponding Dosing Regimens

graphic file with name WNL-2022-201435t1.jpg

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Previous studies showed that renal functions could influence the PK of levetiracetam and oxcarbazepine.28,29 Therefore, remedial regimens were investigated for patients on levetiracetam and oxcarbazepine regimens with altered renal function (eGFR of 30, 60, and 90 mL/min).

In addition, when monotherapy is unsuccessful, combination with other ASMs is often necessary for antiepilepsy treatment. Because the concomitant ASMs may be inducers or inhibitors, their effect was also investigated.

As the formulation of most ASMs is a rapid-release tablet, a half-dose is applicable as the minimum remedial dose unit besides a regular tablet. As for children taking oral suspension or syrup, a dose of 1 mL is applied as the minimum remedial dose unit. Moreover, different dosing intervals (12 and 24 hours) and various delayed dose scenarios were investigated, in which doses were delayed from 1 to 12 or 24 hours with the step of 1 hour after the scheduled time according to the dosing interval.

Under each nonadherence scenario, 1,000 virtual patients were simulated to depict the PK profiles of each ASM. All virtual patients were simulated to have been administered multiple doses of ASMs and reached a steady state before they delay or miss the dose. Meanwhile, if the differences of the total deviation time between 2 remedial regimens were less than 1 hour, these 2 remedial regimens were assumed to be equivalent. In addition, the narrow therapeutic range between trough/peak concentrations of the 10/90 and 20/80 percentiles was investigated.

Web-Based Dashboard

For individual remedial regimens, a web-based dashboard was established using RxODE and Shiny (version 1.5.0) in R. The concentration-time curves of each remedial strategy were plotted by ggplot2 (version 3.2.1). In addition, the detailed deviation time above and below the individual therapeutic range was estimated for each remedial regimen to help the selection of the most appropriate one for the individual patients. Moreover, to apply the dashboard for various clinical settings, a user-defined module was also developed, in which all parameters could be defined flexibly by users.

Standard Protocol Approvals, Registrations, and Patient Consents

No protocol or ethics approval was required for this work because the data are already anonymized, and this work does not involve new patients.

Data Availability

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Results

Population PK Characteristics of ASMs

A total of 16 population PK models for 11 ASMs were identified.28-42 The enrolled patients ranged from 44 in the study of levetiracetam for children42 to 902 in the study of valproic acid for children.41 In all 16 population PK studies, 10 were prospective clinical studies.29,31,34-37,39-42 In addition, studies for carbamazepine, eslicarbazepine, levetiracetam, topiramate, and valproic acid were conducted in multicenters,29,31,36,39-42 in which studies for eslicarbazepine and levetiracetam contained intensive sampling data.31,40,42

For population PK models of ASMs described by a 1-compartment model with first-order absorption and elimination, the concentration at time t (Ct; mg/L) could be estimated according to equation 1 (Eq.1).

graphic file with name WNL-2022-201435m1.jpg

where dose (mg) represents the administered dose; Inline graphic (h−1) represents absorption rate constant; Inline graphic represents the number of doses administered; Inline graphic (h) represents the half-life; t (h) represents the time after the last dose; Inline graphic (L) represents the apparent volume of distribution, and τ (h) represents the dosing interval. The characteristics and parameter estimates of each identified model are summarized in eTable 2 (links.lww.com/WNL/C511).

Remedial Dosing Regimens

The Monte Carlo simulation showed that the recommended remedial regimens were mostly dependent on the delayed time. For typical patients with normal renal function (eGFR of 90 mL/min) taking monotherapy of ASMs, the recommended remedial regimens for various delayed times are summarized in Table 2.

Table 2.

Recommended Remedial Regimens When Delayed n Hours for Typical Patients

graphic file with name WNL-2022-201435t2.jpg

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When the dose was delayed within 2 hours, the whole delayed dose was recommended to be taken immediately, followed by resuming the regular regimens (strategy B) for most ASMs except clobazam. For patients taking clobazam, they were recommended to take half of the missed dose immediately and resume the regular regimens (strategy C) or to take the missed dose immediately and half of the missed dose at the next scheduled time (strategy D) even if the dose was delayed within 2 hours. For adults taking phenytoin, strategy B was only recommended when the dose was delayed within 1 hour. Moreover, for children taking phenytoin, strategies C and D were also recommended when the dose was delayed within 2 hours.

When the delay was more than 2 hours and up to 2 hours before the next scheduled time, strategy C or D was recommended for most ASMs, except phenobarbital and zonisamide. For these, only strategy B was recommended. For the other ASMs, the exact recommended strategy was dependent on the ASM and the patient's demographics. For example, when the delayed time was 4 hours, strategy C was recommended for adults taking levetiracetam, whereas strategy D was recommended for adults taking oxcarbazepine, and both strategies C and D were recommended for children taking oxcarbazepine.

When the dose was delayed within 2 hours to the next dose, one and a half of the missed doses were recommended to be taken immediately (strategy E) for most ASMs, except topiramate and phenytoin. For topiramate and phenytoin, when the dose was missed (delayed 12 hours for q12h dosing), taking only the scheduled dose (strategy A) was recommended. For other ASMs, when the dose was missed (delayed 12 hours for q12h dosing), one and a half of the missed doses were recommended to be taken at the scheduled time (strategy F).

For children taking valproate acid syrup, the minimum remedial dose unit was smaller. Therefore, the recommended remedial regimens could be more precisely restored to the individual therapeutic range. When the dose was delayed within 4 hours, either strategy C or D with a remedial dose of 160 mg (4 mL of syrup) was recommended. When the dose was missed (delayed 12 hours for q12h dosing), strategy F with a remedial dose of either 240 mg (6 mL of syrup) or 280 mg (7 mL of syrup) was recommended. The recommended remedial regimens for children taking syrup or oral solution are summarized in eTable 3 (links.lww.com/WNL/C511).

Impact of Patients' Demographics, Concomitant Medication, and Scheduled Dosing Interval

For most ASMs, the recommended remedial regimens for pediatric (10 years old, 30 kg, and 140 cm) and adult (40 years old, 70 kg, and 180 cm) patients were different. For example, regarding levetiracetam, when the dose was delayed nearly 12 hours, strategy A was recommended for children, whereas strategy F was recommended for adults.

Renal function influenced the apparent clearance (CL/F) of levetiracetam and oxcarbazepine, and the impact on remedial regimens was not the same for those 2 ASMs. For adults taking levetiracetam, similar remedial regimens were recommended for those with eGFR values between 30 and 60 mL/min. As for adults taking oxcarbazepine, the remedial regimens were similar for those with eGFR values between 60 and 90 mL/min. The recommended remedial regimens for adults with various eGFR levels are summarized in eTable 4 (links.lww.com/WNL/C511).

For patients taking ASMs concomitant with inducers such as carbamazepine, phenobarbital, and phenytoin, the recommended remedial strategies were similar to those with monotherapy or with neutral comedications. For children taking lamotrigine and phenobarbital simultaneously, half of the delayed dose was recommended if the dose was delayed between 2 to 3 hours, whereas the whole delayed dose was recommended for those with monotherapy. Moreover, for children taking lamotrigine concomitant with inhibitors such as valproic acid, the whole delayed dose was recommended even the dose was delayed within 7 hours. The recommended remedial regimens for patients with various concomitant medications are summarized in eTable 5 (links.lww.com/WNL/C511).

The remedial regimens were also dependent on the dosing interval. For example, one and a half of missed valproic acid doses were recommended to be taken immediately (strategy F) when it was within 5 hours to the next scheduled dose for q12h and within 2 hours for q24h.

In most scenarios, the recommended remedial regimens for the therapeutic range between trough/peak concentrations of 5/95 percentiles were consistent with those for the trough/peak concentrations of 10/90 percentiles. However, for a narrower therapeutic range between trough/peak concentrations of the 20/80 percentiles, the recommended remedial regimens were altered in approximately 10% of the scenarios (eTable 6, links.lww.com/WNL/C511).

Web-Based Dashboard

The web-based dashboard for individual remedial regimens could be visited online.43 It was also added in the model-informed precision dosing software SmartDose.44 After inputting the patient's demographics, regular dosing regimens, concomitant medication, minimum remedial dose unit, and delayed time, the deviation time outside the individual therapeutic range of all optional remedial regimens could be estimated within a few seconds. By comparing each remedial regimen, the most appropriate remedial dosing regimen could be selected and applied to the individual patient. Because the appropriate individual remedial regimen requires a comprehensive evaluation of both the disease status and nonadherence behavior of the patients, healthy providers are recommended to use this dashboard to avoid patient misuse.

The screenshots of this dashboard are presented in eFigure 2 (links.lww.com/WNL/C511), which indicated the example of a 10-year-old pediatric patient weighing 30 kg and having an eGFR of 90 mL/min, who was taking 300 mg oxcarbazepine monotherapy q12h. Two scenarios including a delayed dose of 2 and 11 hours were investigated in this example. The oxcarbazepine is usually used as the immediate-release tablet, which can be taken by splitting half. Therefore, the minimum dose unit for providing remedial regimens was assumed to be half of the tablet (150 mg).

When the dose was delayed by 2 hours, the simulated PK profiles of all 6 remedial strategies with the deviation time are shown in Figure 3. Strategies A, E, and F yielded a high deviation time above 14 hours and were not recommended. Strategy B (administer 300 mg immediately followed by 300 mg at the next scheduled time) showed a total deviation time of 6.9 hours (4.9 hours above the upper limit + 2.0 hours below the lower limit), strategy C (administer 150 mg immediately followed by 300 mg at the next scheduled time) showed a similar total deviation time of 6.6 hours (0 hours above the upper limit + 6.6 hours below the lower limit), and strategy D (administer 300 mg immediately followed by 150 mg at the next scheduled time) showed a total deviation time of 7.2 hours (7.2 hours below the lower limit + 0 hours above the upper limit).

Figure 3. Concentration-Time Curves of Each Remedial Strategy.

Figure 3

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The dashed lines represent the individual therapeutic range. The bold black lines represent the deviation time outside the individual therapeutic range. A round tablet represents a regular dose, a half-round tablet represents half of the regular dose and a dashed round tablet represents a missed or skipped regular dose. The red line represents the median of simulated concentration-time curves. The pink shadows represent the distribution of the range between the 5th and 95th percentile of the simulated concentrations.

For patients with a high risk of epilepsy recurrence, strategy B with the lowest deviation time below the lower limit was preferred, whereas for patients with low tolerance of adverse drug reactions, strategy C or D with a less deviation time above the upper limit could be more appropriate.

When the dose was delayed by 11 hours, the strategies A, B, C, and F yielded a high deviation time above 14 hours and were not recommended. The total deviation time was 11.9 hours (11.4 hours below the lower limit + 0.5 hours above the upper limit) for strategy D and 12.6 hours (11.2 hours below the lower limit + 1.4 hours above the upper limit) for strategy E (administer 450 mg immediately and skip the next scheduled time).

Therefore, in such a scenario, both strategies D and E were recommended. Moreover, because strategy E recommended taking a large dose immediately, it could rapidly restore to the therapeutic range, which is more proper for patients who have a high risk of seizure recurrence.

The user-defined module is also provided in the dashboard45 In the user-defined module, all PK parameters (absorption rate, apparent clearance, and apparent volume of distribution), unexplained variabilities, and the individual therapeutic range (fixed value or percentile of peak and trough concentration) could be modified as needed. In addition, another remedial strategy could be flexibly defined by the user to alter the dose at the time when they remember the delayed dose and the time of the next scheduled dose.

eFigure 3A (links.lww.com/WNL/C511) showed a specific pediatric patient taking an ASM, who had an absorption rate constant of 0.43 h−1, clearance of 2.6 L/h, and distribution volume of 14.0 L. The between-subject variabilities were set as 20% for each parameter, and the residual unexplained variability was set as 1%. Moreover, the therapeutic window was set as 3–20 mg/L. When the dose was delayed by 2 hours, only strategy B with a total deviation time of 8.9 hours (0 hours above the upper limit + 8.9 hours below the lower limit) was recommended, as shown in eFigure 3B. The deviation time and concentration-time curves of all remedial strategies are present in eFigure 3C.

Discussion

This study aimed to comprehensively provide individualized remedial regimens for delayed or missed doses of commonly used ASMs. The influences of patients' demographics, concomitant medication, and scheduled dosing regimens on remedial regimens were investigated. Moreover, a web-based dashboard was established to facilitate optimal remedial regimens for the individual patient.

There is a clear relationship between exposure and response for the ASMs.22 In 2003, oxcarbazepine was approved by the FDA for the treatment of partial seizures as a monotherapy in children aged 4 years or older based on pharmacokinetic-pharmacodynamic modeling and simulation.46 Moreover, the FDA has recommended and approved the dosing regimens of ASMs in children extrapolated from adults by PK modeling and the simulation approach without the confirmatory clinical trials in 2018.47 This was confirmed by further clinical investigations, and oxcarbazepine was considered a first-line ASM for pediatric patients with partial-onset seizures.3,48 The same approach was used to reliably provide individualized remedial regimens in this study.

For patients with epilepsy, because of the high interindividual variability in the PK characteristics of ASMs, the therapeutic range can differ remarkably from patient to patient. Therefore, the individual therapeutic range was recommended by the International League Against Epilepsy as the range associated with the optimal response in a particular patient,22 which was adopted in this study instead of a fixed reference range. Moreover, in this study, individual therapeutic ranges between trough/peak concentrations of the 5/95, 10/90, and 20/80 percentiles were investigated. Narrower therapeutic ranges led to a larger deviation time and therefore influenced the performance of remedial regimens.

The optimal remedial dosing strategy for nonadherence scenarios was dependent on the half-life of the ASMs in the individual patient. This is consistent with the previous study49 using a theoretical mathematical approach. This could explain the large differences in remedial regimens between adults and pediatric patients because the children showed higher clearance per weight and lower half-life than adult patients.

Moreover, covariates, such as patient demographics and concomitant medications, could influence the individual's PK of the ASMs and thus have an impact on the remedial dosing regimen. In our study, important covariates affecting the half-life of each ASM, which had been identified in the previous population PK studies, were included and evaluated by a modeling and simulation approach. Moreover, our study also incorporated unexplained variabilities in the analysis, which could be modified in the user-defined modules as needed to apply in various clinical settings.

This study systematically examined 6 remedial strategies for the delayed or missed dose. Given that half the regular dose was usually set as the minimum remedial dose, the total dose of each recommended remedial regimen at 2 time points was no higher than 1.5 times the scheduled dose when the dose was delayed more than 5 hours. Other remedial strategies with higher total dosage were not appropriate because of the higher deviation time above the therapeutic range. To explore potential candidate remedial regimens in special scenarios, remedial regimens at 2 time points could be input in the user-defined module of the dashboard.

In our study, strategy B was often recommended in delayed time less than 2 hours. Strategy C or D was often recommended when the delayed time was more than 2 hours and up to 2 hours to the next scheduled time. Moreover, when the dose was delayed within 2 hours to the next dose, strategy E or F was often recommended. The recommendations in this study were consistent with those in previous studies for carbamazepine,16 valproic acid,17 lamotrigine,18 levetiracetam,20 and phenobarbital.21 However, previous studies were limited to only typical patients or scenarios. In our study, we went further to systematically assess the remedial regimens in both children and adults on various concomitant medications and at different pathophysiologic statuses.

In addition, compared with the study assessing remedial regimens for eslicarbazepine,19 we systematically investigated more remedial strategies. For instance, when the dose is delayed between 8 and 20 hours for the dosing interval of 24 hours, strategies C and D both exhibited lower deviation times than strategy B, indicating that strategies C and D were more appropriate in this scenario. However, the strategies C and D were not tested in the previous study.19

When a dose is missed, the FDA recommends to take the missed dose as soon as possible, unless it is almost time for the next dose. However, they do not clearly define the time window for the remedial dosing. In our study, we estimated the appropriate time window for each of the ASMs in various scenarios. Moreover, when it is near the next scheduled dose, the FDA recommends to skip the dose and to not double the dose. However, the accurate time window and how many remedial doses should be taken in such scenarios are not described. Our study showed that skipping the dose when it is near the next dose is not appropriate for most ASMs. Strategies C, D, and E showed a less deviation time and should be considered.

Among all 6 strategies, strategy B usually had a deviation time both above the upper and below the lower limit of the individual therapeutic range, whereas strategy C or D usually had a deviation time only below the lower limit. Therefore, although their total deviation time is close, for patients with a high risk of epilepsy recurrence, strategy B with a less deviation time below the lower limit of the individual therapeutic range is more appropriate. By contrast, patients with a lower tolerance for high concentrations of ASMs should choose the strategies with a less deviation time above the upper limit of the individual therapeutic range (strategy C or D).

Meanwhile, compared with strategy C, strategy D or E could rapidly return the concentration to the therapeutic range. Therefore, for patients who have high seizure frequency, when the total deviation time of strategies C, D, and E is similar, strategy D or E may be more appropriate. In the established dashboard, when it is necessary to select optimal remedial regimens according to the patient's medical records, both the deviation time higher than the upper limit and deviation time lower than the lower limit of the individual therapeutic range could be provided.

In addition, in the user-defined module of the web-based dashboard, the individual PK parameters could be defined by the user according to the Bayesian forecasting with or without therapeutic drug monitoring. Moreover, because the individual therapeutic range may be asymmetric, the upper and lower limit of the therapeutic range could also be defined as needed in the user-defined module. By altering the parameters when necessary, this dashboard could provide more precise remedial regimens for the individual patient in specific situations.

This study still has several limitations. First, only immediate-release tablets, oral suspensions, and syrup formulations were investigated in this study. The extended-release formulations were not assessed because of the lack of population PK studies on these formulations. Second, only remedial regimens for a single delayed or missed dose were established in this study. Multiple missed doses, incorrectly taken doses, and other more complex nonadherence patterns were not considered. Therefore, additional efforts are needed to handle this nonadherence behavior. Last, because few population PK models were based on CNS concentrations of ASMs, only serum concentrations of ASMs were used for the assessment of remedial regimens in this study. Although serum and CNS concentrations are generally comparable, their kinetic characteristics may be different. Further studies targeting the evaluation of CNS concentrations are yet to be explored.

Individual remedial regimens for the delayed or missed ASM dose should be recommended based on the ASMs, patients' demographics, concomitant medication, scheduled dosing intervals, and delayed time. Therefore, a web-based remedial regimen dashboard using a population PK–based Monte Carlo simulation approach has been developed to provide individual remedial regimens for commonly used ASMs.

Acknowledgment

The authors thank Editage (editage.cn) for English language editing.

Glossary

ASM

antiseizure medication

FDA

US Food and Drug Administration

PK

pharmacokinetic

Appendix. Authors

Appendix.

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Study Funding

The authors report no targeted funding.

Disclosure

Zheng Jiao received consulting fees from Takeda, AstraZeneca, and Pharmaron. The other authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

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Associated Data

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Data Availability Statement

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

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