Model‐Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy

乙磺酰亚胺 加药 医学 人口 随机对照试验 丙戊酸 癫痫 拉莫三嗪 不利影响 药代动力学 麻醉 内科学 抗惊厥药 精神科 环境卫生
作者
Kana Mizuno,Edmund V. Capparelli,Tsuyoshi Fukuda,Min Dong,Peter C. Adamson,J Blumer,Avital Cnaan,Peggy O. Clark,Michael D. Reed,Shlomo Shinnar,Alexander A. Vinks,Tracy A. Glauser
出处
期刊:Clinical Pharmacology & Therapeutics [Wiley]
卷期号:114 (2): 459-469 被引量:1
标识
DOI:10.1002/cpt.2965
摘要

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.
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