E-002 - MODEL-INFORMED PRECISION DOSING GUIDANCE OF ETHOSUXIMIDE DEVELOPED FROM A RANDOMIZED CONTROLLED CLINICAL TRIAL OF CHIILDHOOD ABSENCE EPILEPSY.

K. Mizuno¹, E. Capparelli², T. Fukuda¹, M. Dong¹, P. Adamson³, J. Blumer⁴, M. Reed⁵, A. Cnaan⁶, P. Clark⁷, S. Shinnar⁸, A. Vinks⁹, T. Glauser⁷; ¹Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, , , ²Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, , , ³Children's Hospital of Philadelphia, , , ⁴Rainbow Clinical Research Center, Rainbow Babies, and Children's Hospital, and 18 Department of Pediatrics Case Western Reserve University, , , ⁵Rainbow Clinical Research Center, Rainbow Babies, and Children's Hospital, and 18 Department of Pediatrics Case Western Researve University, , , ⁶Children's National Health System, , , ⁷Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children's Hospital Medical Center, , , ⁸Montefiore Medical Center, Albert Einstein College of Medicine, , , ⁹Cincinnati Children's Hospital, Division of Clinical Pharmacology, , .

Background: 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.

Methods: 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.

Results: 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.

Conclusion: We identified the need for adjusted mg/kg dosing in different body weight cohorts. This ethosuximide proposed model-informed precision dosing guidance. The results in this abstract have been published in Clin Pharmacol Ther. 2023;114 (2):459-469.