Effect of Nonadherence on Levetiracetam Pharmacokinetics and Remedial Dose Recommendations Using Monte Carlo Simulations

Methaneethorn, Janthima

doi:10.1007/s13318-022-00774-9

Cited by 5 publications

(3 citation statements)

References 23 publications

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“…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.…”

Section: Discussionsupporting

confidence: 89%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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Handling Delayed or Missed Dose of Antiseizure Medications

Wang

Chen

et al. 2023

Neurology

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Background and Objectives: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.Methods: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.Results: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.Discussion: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.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Handling Delayed or Missed Dose of Antiseizure Medications

Wang

Chen

et al. 2023

Neurology

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“…Up to 20% of patients may compensate for missed doses by clustering their medication use, potentially impacting both seizure control and quality of life 11,41 . Expanding preclinical studies to model various adherent behaviors can offer insights into the complex dynamics between missed doses and breakthrough seizures, enhancing existing models for predicting remedial dosing strategies in response to missed doses of ASM therapy 42 . These datasets can greatly inform and optimize adherence and remedial dosing strategies to reduce complications that arise from unpredictable seizures.…”

Section: Discussionmentioning

confidence: 99%

Temporal relationship between levetiracetam nonadherence and breakthrough seizures in a preclinical model of temporal lobe epilepsy

Guignet,

Vuong,

Martinez

et al. 2023

Epilepsia

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ObjectivePoor medication adherence remains a concern for individuals managing their epilepsy with antiseizure medicines (ASMs); however, ethical concerns around withholding medication make it impossible to study the causal relationship between missed doses and seizures in patients. Previous preclinical studies from our group suggest that mechanistically distinct ASMs have varying degrees of forgiveness when a dose is missed. However, with only a few ASMs studied in the context of nonadherence, we sought to expand on previous work to understand the relationship between levetiracetam (LEV) nonadherence and breakthrough seizures.MethodsChronic oral dosing was initiated in rats with established epilepsy via our automated medication‐in‐food delivery system coupled to 24/7 video‐electroencephalographic recording. Baseline seizure burden was established for 4 weeks before enrolling subjects into a 4‐week treatment period with LEV in a 100% fully adherent (75 mg/kg four times daily) or 50% variably adherent paradigm. The temporal relationship between missed doses and breakthrough seizures was correlated with LEV plasma and brain concentrations in separate cohorts of animals.ResultsFull adherence to LEV significantly improved seizure control by 50% in half of the animals. Poor adherence worsened seizure frequency by 85%, with most rats having more severe seizures that formed in clusters following missed doses. LEV concentrations remained below therapeutic levels (<10 μg/mL) in nonadherent animals, with brain and plasma levels directly correlating with the degree of adherence in a 24‐h period. Missed doses of LEV immediately increased the risk of breakthrough seizures; however, this risk was significantly reduced with improved adherence in a 24‐h period.SignificanceThese findings enhance our understanding of ASM nonadherence in preclinical models, highlighting that the timing of missed doses and their impact on seizures may vary between different ASMs. Notably, LEV demonstrates a robust pharmacokinetic reliance on missed doses leading to breakthrough seizures.

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Simulations of topiramate dosage recommendations for poor compliance events

Methaneethorn

Charoenchokthavee

2022

Eur J Clin Pharmacol

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Effect of Nonadherence on Levetiracetam Pharmacokinetics and Remedial Dose Recommendations Using Monte Carlo Simulations

Cited by 5 publications

References 23 publications

Handling Delayed or Missed Dose of Antiseizure Medications

Handling Delayed or Missed Dose of Antiseizure Medications

Temporal relationship between levetiracetam nonadherence and breakthrough seizures in a preclinical model of temporal lobe epilepsy

Simulations of topiramate dosage recommendations for poor compliance events

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