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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1452526

Population Pharmacokinetic and Pharmacodynamic Model Guided Weight-Tiered Dose of AST-001 in Pediatric Patients with Autism Spectrum Disorder

Provisionally accepted
Soyoung Lee Soyoung Lee 1Su-Kyeong Hwang Su-Kyeong Hwang 2,3Jung-Sook Cho Jung-Sook Cho 3Hyung Chul Ryu Hyung Chul Ryu 3Jae-Yong Chung Jae-Yong Chung 4*
  • 1 Chungnam National University, Daejeon, Daejeon, Republic of Korea
  • 2 Kyungpook National University, Daegu, North Gyeongsang, Republic of Korea
  • 3 Astrogen Inc, Daegu, North Gyeongsang, Republic of Korea
  • 4 Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi, Republic of Korea

The final, formatted version of the article will be published soon.

    AST-001, a novel syrup formulation of L-serine, was developed for the treatment of autism spectrum disorders (ASD) in pediatric patients. This study aimed to establish a pharmacokinetic (PK)-pharmacodynamic (PD) model to elucidate the effect of AST-001 on adaptive behavior in children with ASD. Due to the absence of PK samples in pediatric patients, a previously published population PK model was used to link the PD model by applying an allometric scale to body weight. The time courses of Korean-Vineland Adaptive Behavior Scale-II Adaptive Behavior Composite (K-VABS-II-ABC) scores were best described by an effect compartment model with linear drug effects (Deff, 0.0022 L/μg) and linear progression, where an equilibration half-life to the effect compartment was approximately 15 weeks. Our findings indicated a positive correlation between the baseline K-VABS-II-ABC score (E0, 48.51) and the rate of natural progression (Kprog, 0.015 day -1 ), suggesting enhanced natural behavioral improvements in patients with better baseline adaptive behavior. Moreover, age was identified as a significant covariate for E0 and was incorporated into the model using a power function. Based on our model, the recommended dosing regimens for phase III trials are 2 g, 4 g, 6 g, 10 g, and 14 g, administered twice daily for weight ranges of 10-13, 14-20, 21-34, 35-49, and > 50 kg, respectively. These doses are expected to significantly improve ASD symptoms. This study not only proposes an optimized dosing strategy for AST-001 but also provides valuable insights into the PK-PD relationship in pediatric ASD treatment.

    Keywords: Vineland Adaptive Behavior Scales-II, L-serine, Autism Spectrum Disorder, Weight-Tiered Dose, PK-PD (Pharamacokinetic-Pharmacodynamic) Model

    Received: 21 Jun 2024; Accepted: 27 Nov 2024.

    Copyright: © 2024 Lee, Hwang, Cho, Ryu and Chung. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jae-Yong Chung, Seoul National University Bundang Hospital, Seongnam-si, 13620, Gyeonggi, Republic of Korea

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.