{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:17:54Z","timestamp":1790360274218,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,6,25]],"date-time":"2023-06-25T00:00:00Z","timestamp":1687651200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:p>Ethosuximide was identified as the optimal option for new\u2010onset childhood absence epilepsy (CAE) in a randomized, two\u2010phase dose escalation comparative effectiveness trial of ethosuximide, lamotrigine, and valproic acid. However, 47% of ethosuximide initial monotherapy participants experienced short\u2010term treatment failure. This study aimed to characterize the initial monotherapy ethosuximide exposure\u2010response relationship and to propose model\u2010informed precision dosing guidance. Dose titration occurred over a 16\u201320\u2010week 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 (<jats:italic>n<\/jats:italic>\u2009=\u20091,320), collected at 4\u2010week intervals from 211 unique participants during both the initial and second monotherapy phases. A logistic regression analysis was performed on the initial monotherapy cohort (<jats:italic>n<\/jats:italic>\u2009=\u2009103) with complete exposure\u2010response data. Eighty\u2010four participants achieved seizure freedom with a wide range of ethosuximide area under the curves (AUC) ranging from 420 to 2,420\u2009\u03bcg\u00b7h\/mL. AUC exposure estimates for achieving a 50% and 75% probability of seizure freedom were 1,027 and 1,489\u2009\u03bcg\u00b7h\/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\u2009mg\/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\u2010informed precision dosing guidance to achieve seizure freedom carries promise to optimize initial monotherapy success for patients with CAE.<\/jats:p>","DOI":"10.1002\/cpt.2965","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T02:25:25Z","timestamp":1686795925000},"page":"459-469","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Model\u2010Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3154-7477","authenticated-orcid":false,"given":"Kana","family":"Mizuno","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati  Cincinnati 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