Abstract
Li ZR, Wang CY, Lin WW, Chen YT, Liu XQ, Jiao Z. Neurology. 2023;100(9):e921-e931. doi:10.1212/WNL.0000000000201604
Antiseizure medications are the major treatment modality for patients with epilepsy. Delayed or missed doses are common during long-term or lifelong anti-epilepsy treatment. This study aims to explore optimal individualized remedial dosing regimens for delayed or missed doses of 11 commonly used antiseizure medications. In order to explore remedial dosing regimens, Monte Carlo simulation was employed 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 employed to perform Monte Carlo simulation and recommend individual remedial regimens. The recommended remedial regimens were highly correlated to delayed time, scheduled dosing interval, and half-life of the antiseizure medication. Moreover, the optimal remedial regimens for pediatric and adult patients were different. The renal function, along with concomitant medication that affect the clearance of the antiseizure medication, 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. Monte Carlo simulation based on population pharmacokinetic models may provide a rational approach to propose remedial regimens for delayed or missed doses of antiseizure medications in pediatric and adult patients with epilepsy.Background and Objectives:
Methods:
Results:
Discussion:
Commentary
We are fortunate as epilepsy providers to have a wide variety of effective treatment choices. Yet, there are many barriers preventing perfect adherence to anti-seizure medications (ASMs). The result is that 30% to 50% of patients may be classified as “nonadherent” to prescribed treatment 1 with potentially serious adverse outcomes. 2,3 Thus, it is imperative to enact feasible, scalable, strategies to mitigate the consequences of nonadherence.
Literature typically has approached this question by assessing barriers to or predictors of nonadherence, 4,5 hoping to uncover modifiable preventable factors. It is true as they say: “An ounce of prevention is worth a pound of cure.” Still, multidisciplinary behavioral interventions can be time and resource intensive, and smartwatch reminders and apps are promising but also require specific technology, which may not always be available.
This brings up a very practical question—What do you tell patients to do if/when they miss a dose? Here is some advice that may sound familiar—take the dose soon as possible, unless it is near the next scheduled dose in which case just skip the missed dose without doubling up. This is reflected in FDA labels and published patient materials 6 and has decent face validity. We don’t want levels to drop too low, but on the other hand taking 2 doses at once might produce brief but unwanted side effects.
The problem, though, is that this advice is not evidence-based. Some population pharmacokinetic studies have assessed what pharmacokinetics would predict to be an optimal “remedial” dosing strategy but have used time-intensive specialized software not available to clinicians, in only a limited number of patient or drug scenarios. The result is that nobody knows how close to the next dose is “too close” to take the missed dose. And why not shades of gray, such as taking 1.5 doses or 0.5 makeup doses depending on the situation, rather than double or nothing?
Li et al
7
expanded upon previous studies by using existing pharmacokinetic data to show how ASM concentration curves fluctuate over time (how much time spent outside of the desired therapeutic range) for 12 different ASMs, in response to 6 different hypothetical “remediation” strategies, for adults versus children, at different intervals since the missed dose, for different renal function, using complex Monte Carlo simulations. They tested out 6 strategies: Skip the missed dose. Take the missed dose immediately. Take 0.5 of the missed dose immediately. Take the missed dose immediately, but just 0.5 doses at the next regularly scheduled time. Take 1.5 doses immediately, then skip the next regularly scheduled dose. Skip the missed dose, then take 1.5 doses at the next regularly scheduled time.
In short, the standard advice involves either B if not too long since the missed dose, or else A it has been “too long” since the missed dose. Strategies C-F might all be considered “experimental” conditions, not usually currently advised in practice, each involving either 0.5 or 1.5 doses.
One relatively consistent conclusion was that completely skipping a missed dose (strategy A) and just resuming with the next scheduled dose is usually not the best answer, even if close to the next dose (despite this being current typical advice). Rather, most of the time they found that various shades of either making up 0.5 dose immediately (strategy C), taking a full immediate dose then taking 0.5 dose at the next scheduled time (strategy D), or else just taking 1.5 now versus later (strategies E or F) outperformed strategy A. There were a few exceptions. For example, strategy A did minimize time outside the desired concentration range for phenytoin and topiramate for both adults and children, if remembered not until a couple hours of the next dose.
The other question is whether to take the full missed dose immediately if remembered soon enough. They found that for most ASMs, taking the full missed dose immediately did minimize time outside the desired therapeutic range if taken within a few hours of the missed dose. This makes sense and is in line with the above usual advice. There were just a couple exceptions—for example, clobazam (with its long half-life) was better served by any of the “0.5” or “1.5” dose strategies if a dose is anything more than 1 hour delayed.
Take a typical example—twice daily levetiracetam, assume a 40-year-old adult with normal renal function. Their results endorse some of our typical advice—take the full missed dose immediately if remembered within 2 hours of the scheduled time (our typical advice, strategy B). But if remembered more than 2 hours after the originally scheduled time, their results favored different variations of making up only half of the missed dose (strategies C-F), rather than skipping an entire dose.
They have posted their results in a convenient online format (https://make-up-dose.shinyapps.io/shinyapp/). This allows the user to take matters into their own hands by entering a patient’s specific data into this app to view how concentrations may fluctuate under strategies A-F. For more advanced users, they posted another app (https://make-up-dose-user-defined.shinyapps.io/shinyapp2/) in which one can even modify assumptions about absorption, clearance, volume of distribution, and more.
Even with their large array of analyses, the investigators could look at only a subset of all possible ASMs or ages (they did not include a scenario for older patients, for whom changes in renal function and susceptibility to adverse effects may be greatest), and these data pertain only to immediate rather than extended-release formulations. There are also 2 elephants in the room: (1) Translating a precise sinusoidal concentration curve into the chance that a patient might have seizures or side effects is not simple, nor does this inform how the patient perceives the tradeoff between transient seizure versus side effect risk, and (2) None of this modeling addresses the underlying cause of skipping doses.
That said, this is a nicely done, useful study, involving incredible technical demands. But what I most appreciate about this study is its spirit. The investigators identified an extremely common clinical scenario with agreed upon yet arbitrary guidance and sought to provide clinicians with freely available evidence-based guideposts.
