Population Pharmacokinetic Model of AST-001, L-Isomer of Serine, Combining Endogenous Production and Exogenous Administration in Healthy Subjects

Lee, Soyoung; Hwang, Su-Kyeong; Nam, Hee-Sook; Cho, Jung-Sook; Chung, Jae‐Yong

doi:10.3389/fphar.2022.891227

Cited by 3 publications

(2 citation statements)

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“…To evaluate the efficacy of AST-001 on autistic-like behavior, AST-001 was orally administered to VPA-exposed model mice on postnatal day 21 for 2 weeks, and 3-chamber sociability and social novelty tests were performed (Figure 3A). The dosage was referenced from our previous pharmacokinetics studies of AST-001 in healthy human subjects [19]. Sociability is measured using the preference between strangers and objects (Figure 3B,C).…”

Section: Ast-001 Improves Social Interaction In Asd Mouse Modelsmentioning

confidence: 99%

“…AST-001 is an L-isomer of serine (L-Serine, patents related to AST-001 include Korean Patent No. 2091620 and PCT/KR2022/003789) [19], a conditionally essential amino acid for the brain, because it acts as a neurotrophic factor, including neuronal signaling, neuroprotection, development, and proliferation [20]. L-Serine is known to be effective in neurological diseases such as epilepsy, schizophrenia, and Alzheimer's Disease [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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AST-001 Improves Social Deficits and Restores Dopamine Neuron Activity in a Mouse Model of Autism

Um,

Kwak,

Cheon

et al. 2023

Biomedicines

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social communication and social interaction, restricted and repetitive behavior, and interests. The core symptoms of ASD are associated with deficits in mesocorticolimbic dopamine pathways that project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). AST-001 is an investigational product currently in a phase 3 clinical trial for treating the core symptoms of ASD, with L-serine as the API (active pharmaceutical ingredient). Because the causes of ASD are extremely heterogeneous, a single genetic ASD model cannot represent all autism models. In this paper, we used the VPA-exposed model, which is more general and widely used than a single genetic model, but this is also one of the animal models of autism. Herein, we conducted experiments to demonstrate the efficacy of AST-001 as L-Serine that alters the regulation of the firing rate in dopamine neurons by inhibiting small conductance Ca2+-activated K+ channels (SK channels). Through these actions, AST-001 improved sociability and social novelty by rescuing the intrinsic excitabilities of dopamine neurons in VPA-exposed ASD mouse models that showed ASD-related behavioral abnormalities. It is thought that this effect of improving social deficits in VPA-exposed ASD mouse models is due to AST-001 normalizing aberrant SK channel activities that slowed VTA dopamine neuron firing. Overall, these findings suggest that AST-001 may be a potential therapeutic agent for ASD patients, and that its mechanism of action may involve the regulation of dopamine neuron activity and the improvement of social interaction.

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Section: Ast-001 Improves Social Interaction In Asd Mouse Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AST-001 Improves Social Deficits and Restores Dopamine Neuron Activity in a Mouse Model of Autism

Um,

Kwak,

Cheon

et al. 2023

Biomedicines

Self Cite

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AST‐001 versus placebo for social communication in children with autism spectrum disorder: A randomized clinical trial

Kim,

Chung

et al. 2024

Psychiatry Clin Neurosci

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AimThis study examined the efficacy of AST‐001 for the core symptoms of autism spectrum disorder (ASD) in children.MethodsThis phase 2 clinical trial consisted of a 12‐week placebo‐controlled main study, a 12‐week extension, and a 12‐week follow‐up in children aged 2 to 11 years with ASD. The participants were randomized in a 1:1:1 ratio to a high‐dose, low‐dose, or placebo‐to‐high‐dose control group during the main study. The placebo‐to‐high‐dose control group received placebo during the main study and high‐dose AST‐001 during the extension. The a priori primary outcome was the mean change in the Adaptive Behavior Composite (ABC) score of the Korean Vineland Adaptive Behavior Scales II (K‐VABS‐II) from baseline to week 12.ResultsAmong 151 enrolled participants, 144 completed the main study, 140 completed the extension, and 135 completed the follow‐up. The mean K‐VABS‐II ABC score at the 12th week compared with baseline was significantly increased in the high‐dose group (P = 0.042) compared with the placebo‐to‐high‐dose control group. The mean CGI‐S scores were significantly decreased at the 12th week in the high‐dose (P = 0.046) and low‐dose (P = 0.017) groups compared with the placebo‐to‐high‐dose control group. During the extension, the K‐VABS‐II ABC and CGI‐S scores of the placebo‐to‐high‐dose control group changed rapidly after administration of high‐dose AST‐001 and caught up with those of the high‐dose group at the 24th week. AST‐001 was well tolerated with no safety concern. The most common adverse drug reaction was diarrhea.ConclusionsOur results provide preliminary evidence for the efficacy of AST‐001 for the core symptoms of ASD.

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Population pharmacokinetic and pharmacodynamic model guided weight-tiered dose of AST-001 in pediatric patients with autism spectrum disorder

Lee,

Hwang,

Cho

et al. 2024

Front. Pharmacol.

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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, 4, 6, 10, 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.

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Population Pharmacokinetic Model of AST-001, L-Isomer of Serine, Combining Endogenous Production and Exogenous Administration in Healthy Subjects

Cited by 3 publications

References 40 publications

AST-001 Improves Social Deficits and Restores Dopamine Neuron Activity in a Mouse Model of Autism

AST-001 Improves Social Deficits and Restores Dopamine Neuron Activity in a Mouse Model of Autism

AST‐001 versus placebo for social communication in children with autism spectrum disorder: A randomized clinical trial

Population pharmacokinetic and pharmacodynamic model guided weight-tiered dose of AST-001 in pediatric patients with autism spectrum disorder

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