Advanced Model-Based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers

Clin Ther. 2024 Mar 13:S0149-2918(24)00009-2. doi: 10.1016/j.clinthera.2023.12.015. Online ahead of print.ABSTRACTPURPOSE: NV-5138 ([S]-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid) is an orally bioavailable, small-molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in development for treatment-resistant depression. The authors established a model to describe the relationship between plasma and cerebrospinal fluid (CSF) concentrations of NV-5138 and between CSF concentrations and potential biomarkers thought to be associated with mTORC1 activity (ie, orotic acid, N-acetylmethionine, and N-formylmethionine).METHODS: Data were collected from a randomized, double-blind, placebo-controlled, tolerability, and pharmacokinetic (PK) parameter study of 5 ascending (400, 800, 1600, 2400, and 3000 mg), once-daily oral doses of NV-5138 in healthy subjects. NV-5138 plasma PK parameter samples were collected at 15 time points over 24 hours on days 1 and 7, and at pre dose on days 2-6 for all doses. NV-5138 CSF PK parameter and CSF biomarker samples were collected on days 1 and 7 at pre dose and 4, 8, and 12 hours post dose for all doses except 3000 mg. A model-based approach was used to develop and validate a model that describes the relationship between NV-5138 in CSF and biomarker concentrations.FINDINGS: Twenty-four of the 42 enrolled subjects had simultaneous plasma and CSF measurements of NV-5138 and CSF biomarker concentrations and were included in...
Source: Clinical Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research