Model-Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy
© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:114 |
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| Enthalten in: |
Clinical pharmacology and therapeutics - 114(2023), 2 vom: 28. Aug., Seite 459-469 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mizuno, Kana [VerfasserIn] |
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| Links: |
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| Themen: |
5SEH9X1D1D |
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| Anmerkungen: |
Date Completed 23.10.2023 Date Revised 24.10.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/cpt.2965 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM358180651 |
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| 520 | |a 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 | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a 5SEH9X1D1D |2 NLM | |
| 650 | 7 | |a Anticonvulsants |2 NLM | |
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| 700 | 1 | |a Capparelli, Edmund V |e verfasserin |4 aut | |
| 700 | 1 | |a Fukuda, Tsuyoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Adamson, Peter C |e verfasserin |4 aut | |
| 700 | 1 | |a Blumer, Jeffery L |e verfasserin |4 aut | |
| 700 | 1 | |a Cnaan, Avital |e verfasserin |4 aut | |
| 700 | 1 | |a Clark, Peggy O |e verfasserin |4 aut | |
| 700 | 1 | |a Reed, Michael D |e verfasserin |4 aut | |
| 700 | 1 | |a Shinnar, Shlomo |e verfasserin |4 aut | |
| 700 | 1 | |a Vinks, Alexander A |e verfasserin |4 aut | |
| 700 | 1 | |a Glauser, Tracy A |e verfasserin |4 aut | |
| 700 | 0 | |a Childhood Absence Epilepsy Study Group |e verfasserin |4 aut | |
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