Research Horizons


Absence Epilepsy Study Group Provides Dosing Guidance for Ethosuximide

Translational and Clinical Pharmacology | Top Scientific Achievement
2023 Research Discoveries This graphical abstract describes how pharmacokinetics and related technologies can be used to maximize the effectiveness of ethosuximide in seizure prevention.

In 2012, research led by Tracy Glauser, MD, and colleagues with the Childhood Absence Epilepsy Study Group identified the anticonvulsant medication ethosuximide as the optimal option for new-onset childhood absence epilepsy rather than lamotrigine and valproic acid. A decade later, a new study from the group, also led by Glauser, provides important precision dosing recommendations aimed at reducing a significant rate of seizures continuing after initial monotherapy.

The clinical trial involved building quantitative pharmacology models to describe pharmacokinetics and exposure-seizure-free response to inform precision dosing for initial ethosuximide monotherapy. Plasma concentration data were collected from 211 total participants. Dose titration occurred over a 16–20-week period until patients experienced seizure freedom or intolerable side effects. Based on an initial monotherapy cohort of 103 participants, 84 achieved seizure freedom within a wide range of ethosuximide exposure, shown as area under the curves (AUC).

Overall, AUC estimates to reach seizure freedom ranged from 420 to 2,420 micrograms per milliliter per hour (μg·h/ mL). The team found that when the AUC reached 1,027 μg·h/ mL, patients had a 50% probability of seizure freedom, while 1,489 μg·h/mL produced a 75% probability. The corresponding frequency of intolerable adverse events was 11% and 16%, respectively.

The co-authors report that achieving the targeted exposure levels requires a daily dose of 40 mg/kg to achieve a 50% probability of seizure freedom, while 55 mg/kg offers a 75% probability.

“This model-informed guidance suggests that many/ some/most patients receiving ethosuximide as a monotherapy but not achieving seizure freedom may have been under-dosed at treatment onset,” Glauser says. “Employing this new model offers the potential to optimize therapy success for children with absence epilepsy.”

Co-authors included Cincinnati Children’s experts Alexander Vinks, PharmD, PhD, Min Dong, PhD, Tsuyoshi Fukuda, PhD, Peggy Clark, MSN, APRN, PNP, and Kana Mizuno, PhD (first author). Colleagues also contributed from Children’s Hospital of Philadelphia, University of California San Diego, Rainbow Babies and Children’s Hospital in Cleveland, Montefiore Medical Center in New York, and Children’s National Health System in Washington, DC.

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Publication Information
Original title: Model-Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy
Published in: Clinical Pharmacology and Therapeutics
Publish date: June 14, 2023
Read the study

Research By

Kana Mizuno, PhD
Kana Mizuno, PhD
Division of Translational and Clinical Pharmacology
Tracy Glauser, MD
Tracy Glauser, MD
Associate Director, Cincinnati Children's Research Foundation

An expert in neurology, clinical pharmacology and genomics, Dr. Glauser’s research focuses on clinical pharmacology, pharmacogenetics and antiepileptic clinical trials.