Population Pharmacokinetic and Exposure–dizziness Modeling for a Metabotropic Glutamate Receptor Subtype 5 Negative Allosteric Modulator in Major Depressive Disorder Patients

Cosson, Valérie; Schaedeli‐Stark, Franziska; Arab‐Alameddine, Mona; Chavanne, Clarisse; Guerini, Elena; Derks, Michael; Mallalieu, Navita L.

doi:10.1111/cts.12566

Cited by 5 publications

(3 citation statements)

References 21 publications

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“…It participates in physiological processes such as the plastic changes of learning, memorizing, and synaptic transmission efficiency ( Francesconi et al, 2004 ). Studies have found that mGluR5mRNA is associated with schizophrenia ( Matosin et al, 2018 ), depression ( Cosson et al, 2018 ), autism ( D’Antoni et al, 2014 ), Parkinson’s ( Vallano et al, 2013 ), Alzheimer’s ( Zhang et al, 2019 ), and many other neurological diseases. There are three subtypes of NMDAR—NR1, NR2, and NR3—among which NR1 plays a more extensive role ( Zhao et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of the Radix Ginseng and Semen Ziziphi Spinosae drug pair on the GLU/GABA-GLN metabolic cycle and the intestinal microflora of insomniac rats based on the brain–gut axis

et al. 2022

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Introduction: To explore the mechanism of action of appling Radix Ginseng and Semen Ziziphi Spinosae Drug pair (R-S) in the treatment of insomnia by investigating the effect of R-S on GLU/GABA-GLN metabolic cycle and intestinal microflora of rats with insomnia.Methods: Rats were intraperitoneally injected with 4-chloro-DL-phenylalanine (PCPA) to make sleep deprivation (SD) models. The rats were divided into 6 groups, with 8 rats in each group. The general status of the rats was observed and the pentobarbital sodium sleep synergy experiment was performed. The contents of GABA, GLU, GLN, GAD65, and GS in hippocampus of rats were determined by ELISA. The expressions of GABAARα1mRNA, mGluR5mRNA, NR1mRNA and GluR1mRNA in rats’ hippocampal tissue were determined by Realtime PCR. 16SrRNA gene sequencing was used to analyze the intestinal microflora of insomnia rats.Results: In PCPA-induced insomnia rats, the state of insomnia was relieved, the sleep rate was improved, the duration of sleep latency was shortened and the sleep duration was prolonged in each dose group of R-S (p < 0.05, p < 0.01) compared with the model group. The contents of GABA, GLN, GAD65 and GS were increased (p < 0.05, p < 0.01) while GLU content was decreased (p < 0.01) in both medium and high dose groups, especially in the high dose group. The expression of GABAARα1mRNA was increased (p < 0.01), and the expressions of mGluR5mRNA, NR1mRNA and GluR1mRNA were decreased (p < 0.01) in hippocampal tissue of rats in R-S groups, especially in the high dose group. At the same time, the various dose groups of R-S could improve the species diversity, microflora abundance of insomnia rats and regulate the KEGG metabolic pathway related to sleep.Discussion: R-S can improve the sleep of PCPA-induced insomnia rats by regulating GLU/GABA-GLN metabolic cycle and intestinal microflora, which provides experimental basis for appling R-S in the treatment of insomnia.

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Section: Discussionmentioning

confidence: 99%

Effects of the Radix Ginseng and Semen Ziziphi Spinosae drug pair on the GLU/GABA-GLN metabolic cycle and the intestinal microflora of insomniac rats based on the brain–gut axis

et al. 2022

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“…There was an unusually high placebo response rate in this trial. Pooled pharmacokinetic data from four phase I and one phase II studies also suggested that clearance was twofold higher in smokers and 40% higher in males [175]. Due to the negative results on the phase IIb study conducted, this drug has not been cleared by FDA to be used for refractory MDD.…”

Section: Metabotropic Glutamate Receptor Negative Modulationmentioning

confidence: 99%

Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression

Vecera,

C. Courtes,

Jones

et al. 2023

Pharmaceuticals

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Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, L-glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABAA receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study.

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“…As understanding exposure-mGlu 5 RO relationships is important in achieving the right level of mGlu 5 target engagement for positive efficacy in a therapeutic setting, we studied the plasma and brain exposure-RO relationships of dipraglurant, basimglurant, mavoglurant, and HTL0014242, a new mGlu 5 -selective NAM (Christopher et al, 2015). The comparative data for this analysis are derived from experimental data and supplemented by published mGlu 5 RO and exposure data across species (Bennett et al, 2014;Lindemann et al, 2015;Quiroz et al, 2016;Tison et al, 2016;Cosson et al, 2018). As this study will demonstrate, when accounting for mGlu 5 affinity and brain exposure, exposure-RO relationships were similar across species and different mGlu 5 NAMs and in agreement with the simple E max model.…”

Section: Introductionmentioning

confidence: 99%

Understanding Exposure-Receptor Occupancy Relationships for Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators across a Range of Preclinical and Clinical Studies

Bennett

Sergeev

MacSweeney

et al. 2021

J Pharmacol Exp Ther

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The metabotropic glutamate receptor 5 (mGlu 5 ) is a recognized central nervous system therapeutic target for which several negative allosteric modulator (NAM) drug candidates have or are continuing to be investigated for various disease indications in clinical development. Direct measurement of target receptor occupancy (RO) is extremely useful to help design and interpret efficacy and safety in nonclinical and clinical studies. In the mGlu 5 field, this has been successfully achieved by monitoring displacement of radiolabeled ligands, specifically binding to the mGlu 5 receptor, in the presence of an mGlu 5 NAM using in vivo and ex vivo binding in rodents and positron emission tomography imaging in cynomolgus monkeys and humans. The aim of this study was to measure the RO of the mGlu 5 NAM HTL0014242 in rodents and cynomolgus monkeys and to compare its plasma and brain exposure-RO relationships with those of clinically tested mGlu 5 NAMs dipraglurant, mavoglurant, and basimglurant. Potential sources of variability that may contribute to these relationships were explored. Distinct plasma exposure-response relationships were found for each mGlu 5 NAM, with .100-fold difference in plasma exposure for a given level of RO. However, a unified exposure-response relationship was observed when both unbound brain concentration and mGlu 5 affinity were considered. This relationship showed ,10-fold overall difference, was fitted with a Hill slope that was not significantly different from 1, and appeared consistent with a simple E max model. This is the first time this type of comparison has been conducted, demonstrating a unified brain exposure-RO relationship across several species and mGlu 5 NAMs with diverse properties. SIGNIFICANCE STATEMENTDespite the long history of mGlu 5 as a therapeutic target and progression of multiple compounds to the clinic, no formal comparison of exposure-receptor occupancy relationships has been conducted. The data from this study indicate for the first time that a consistent, unified relationship can be observed between exposure and mGlu 5 receptor occupancy when unbound brain concentration and receptor affinity are taken into account across a range of species for a diverse set of mGlu 5 negative allosteric modulators, including a new drug candidate, HTL0014242.

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Population Pharmacokinetic and Exposure–dizziness Modeling for a Metabotropic Glutamate Receptor Subtype 5 Negative Allosteric Modulator in Major Depressive Disorder Patients

Cited by 5 publications

References 21 publications

Effects of the Radix Ginseng and Semen Ziziphi Spinosae drug pair on the GLU/GABA-GLN metabolic cycle and the intestinal microflora of insomniac rats based on the brain–gut axis

Effects of the Radix Ginseng and Semen Ziziphi Spinosae drug pair on the GLU/GABA-GLN metabolic cycle and the intestinal microflora of insomniac rats based on the brain–gut axis

Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression

Understanding Exposure-Receptor Occupancy Relationships for Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators across a Range of Preclinical and Clinical Studies

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