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Background and Objectives <p>ES-481 is a potent and selective antagonist of the transmembrane alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor regulatory protein (TARP)-y8-dependent AMPA receptor being developed for the treatment of drug-resistant epilepsy (DRE). The objective of this study was to determine the pharmacokinetics and tolerability of ES-481 in humans.</p> Methods <p>This study was a Phase 1, first-in-human, single-center, open-label, randomized, sentinel design, ascending dose study of ES-481 to evaluate the pharmacokinetics and tolerability of ES-481 in healthy subjects, with single oral doses ranging from 3 mg to 100 mg. There were 10 dosing cohorts, each comprised of 8 subjects. Within each cohort, 6 subjects were randomized to treatment with ES-481 and 2 subjects were randomized to placebo. In all dosing cohorts, a sentinel pair was dosed first, where 1 subject received ES-481 and 1 subject received a placebo. The sentinel subjects were observed for a minimum of 24 h. If no safety concerns were identified after 24 h, then the remaining 6 subjects in each dosing cohort were administered the investigational product (5 subjects administered ES-481 and 1 subject administered a placebo). In one cohort, only 5 subjects were treated with ES-481. A total of 79 subjects were administered the investigational product (ES-481 or placebo) instead of 80. Blood samples were obtained from each subject up to 48&lt;h post-dose. Following quantification of the concentration of ES-481, pharmacokinetic parameters were derived from plasma concentration–time data using a noncompartmental model.</p> Results <p>An approximately proportional increase in AUC parameters and <i>C</i><sub>max</sub> was observed for ES-481 doses of 3 mg, 6 mg, 12 mg, 25 mg, 37 mg, 50 mg, and 62 mg. Following dosing with 75 mg ES-481, 87 mg ES-481, and 100 mg ES-481, plasma ES-481 concentrations did not increase proportionately. The <i>T</i><sub>max</sub> was observed between 1 h and 4 h post-dose across the dose range examined. Mean (SD) <i>t</i><sub>½</sub> ranged from 6.456 (2.4379) h to 9.846 (3.8931) h. Mean CL/F was consistent between the treatment groups, with mean values at around 10 L/h. Mean (SD) <i>V</i>z/<i>F</i> ranged from 83.514 (20.7577) L in the 12-mg ES-481 treatment group, to 163.903 (84.3912) L in the 100-mg ES-481 treatment group. Exploratory dose proportionality analysis revealed that AUC parameters (AUC<sub>0–last</sub> and AUC<sub>0–inf</sub>) satisfied the interval criterion. <i>C</i><sub>max</sub> did not satisfy the criterion for a proportional response to dose.</p> Conclusions <p>ES-481 doses up to 100 mg were found to be safe and well tolerated. There were no safety findings in this study of concern, and all of the adverse events related to the administration of ES-481 were mild and transient This study describes the pharmacokinetic parameters of ES-481 for the proposed efficacious dose range of 75–100 mg/day of ES-481 for the treatment of DRE.</p>

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A Phase 1, Open-Label, Single Ascending Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of ES-481 After Oral Administration in Healthy Volunteers

  • 期刊论文

  • 发表日期：

    2026年1月5日

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  • Robert Niecestro,
  • Emma C. Foster,
  • Lyn Millist,
  • Jack Germaine,
  • Aaron Niecestro,
  • Terence J. O’Brien

摘要

Background and Objectives

ES-481 is a potent and selective antagonist of the transmembrane alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor regulatory protein (TARP)-y8-dependent AMPA receptor being developed for the treatment of drug-resistant epilepsy (DRE). The objective of this study was to determine the pharmacokinetics and tolerability of ES-481 in humans.

Methods

This study was a Phase 1, first-in-human, single-center, open-label, randomized, sentinel design, ascending dose study of ES-481 to evaluate the pharmacokinetics and tolerability of ES-481 in healthy subjects, with single oral doses ranging from 3 mg to 100 mg. There were 10 dosing cohorts, each comprised of 8 subjects. Within each cohort, 6 subjects were randomized to treatment with ES-481 and 2 subjects were randomized to placebo. In all dosing cohorts, a sentinel pair was dosed first, where 1 subject received ES-481 and 1 subject received a placebo. The sentinel subjects were observed for a minimum of 24 h. If no safety concerns were identified after 24 h, then the remaining 6 subjects in each dosing cohort were administered the investigational product (5 subjects administered ES-481 and 1 subject administered a placebo). In one cohort, only 5 subjects were treated with ES-481. A total of 79 subjects were administered the investigational product (ES-481 or placebo) instead of 80. Blood samples were obtained from each subject up to 48<h post-dose. Following quantification of the concentration of ES-481, pharmacokinetic parameters were derived from plasma concentration–time data using a noncompartmental model.

Results

An approximately proportional increase in AUC parameters and Cmax was observed for ES-481 doses of 3 mg, 6 mg, 12 mg, 25 mg, 37 mg, 50 mg, and 62 mg. Following dosing with 75 mg ES-481, 87 mg ES-481, and 100 mg ES-481, plasma ES-481 concentrations did not increase proportionately. The Tmax was observed between 1 h and 4 h post-dose across the dose range examined. Mean (SD) t½ ranged from 6.456 (2.4379) h to 9.846 (3.8931) h. Mean CL/F was consistent between the treatment groups, with mean values at around 10 L/h. Mean (SD) Vz/F ranged from 83.514 (20.7577) L in the 12-mg ES-481 treatment group, to 163.903 (84.3912) L in the 100-mg ES-481 treatment group. Exploratory dose proportionality analysis revealed that AUC parameters (AUC0–last and AUC0–inf) satisfied the interval criterion. Cmax did not satisfy the criterion for a proportional response to dose.

Conclusions

ES-481 doses up to 100 mg were found to be safe and well tolerated. There were no safety findings in this study of concern, and all of the adverse events related to the administration of ES-481 were mild and transient This study describes the pharmacokinetic parameters of ES-481 for the proposed efficacious dose range of 75–100 mg/day of ES-481 for the treatment of DRE.