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- Title
Model‐Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy.
- Authors
Mizuno, Kana; Capparelli, Edmund V.; Fukuda, Tsuyoshi; Dong, Min; Adamson, Peter C.; Blumer, Jeffery L.; Cnaan, Avital; Clark, Peggy O.; Reed, Michael D.; Shinnar, Shlomo; Vinks, Alexander A.; Glauser, Tracy A.
- Abstract
Ethosuximide was identified as the optimal option for new‐onset childhood absence epilepsy (CAE) in a randomized, two‐phase dose escalation comparative effectiveness trial of ethosuximide, lamotrigine, and valproic acid. However, 47% of ethosuximide initial monotherapy participants experienced short‐term treatment failure. This study aimed to characterize the initial monotherapy ethosuximide exposure‐response relationship and to propose model‐informed precision dosing guidance. Dose titration occurred over a 16–20‐week period until patients experienced seizure freedom or intolerable side effects. Subjects with initial monotherapy failure were randomized to one of the other two medications and dose escalation was repeated. A population pharmacokinetic model was created using plasma concentration data (n = 1,320), collected at 4‐week intervals from 211 unique participants during both the initial and second monotherapy phases. A logistic regression analysis was performed on the initial monotherapy cohort (n = 103) with complete exposure‐response data. Eighty‐four participants achieved seizure freedom with a wide range of ethosuximide area under the curves (AUC) ranging from 420 to 2,420 μg·h/mL. AUC exposure estimates for achieving a 50% and 75% probability of seizure freedom were 1,027 and 1,489 μg·h/mL, respectively, whereas the corresponding cumulative frequency of intolerable adverse events was 11% and 16%. Monte Carlo Simulation indicated a daily dose of 40 and 55 mg/kg to achieve 50% and 75% probability of seizure freedom in the overall population, respectively. We identified the need for adjusted mg/kg dosing in different body weight cohorts. This ethosuximide proposed model‐informed precision dosing guidance to achieve seizure freedom carries promise to optimize initial monotherapy success for patients with CAE.
- Subjects
CHILDHOOD epilepsy; CLINICAL trials; RANDOMIZED controlled trials; MONTE Carlo method; VALPROIC acid
- Publication
Clinical Pharmacology & Therapeutics, 2023, Vol 114, Issue 2, p459
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1002/cpt.2965