scholarly journals (+)-9-Trifluoroethoxy-α-Dihydrotetrabenazine as a Highly Potent Vesicular Monoamine Transporter 2 Inhibitor for Tardive Dyskinesia

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenyan Wang ◽  
Guangying Du ◽  
Shilan Lin ◽  
Jing Liu ◽  
Huijie Yang ◽  
...  
Keyword(s):  
Tardive Dyskinesia ◽  
Cell Monolayer ◽  
Absolute Bioavailability ◽  
Vesicular Monoamine Transporter ◽  
Dependent Manner ◽  
Monoamine Transporter ◽  
Vesicular Monoamine Transporter 2 ◽  
Glucuronide Conjugation ◽  
Dog Plasma

Valbenazine and deutetrabenazine are the only two therapeutic drugs approved for tardive dyskinesia based on blocking the action of vesicular monoamine transporter 2 (VMAT2). But there exist demethylated inactive metabolism at the nine position for both them resulting in low availability, and CYP2D6 plays a major role in this metabolism resulting in the genetic polymorphism issue. 9-trifluoroethoxy-dihydrotetrabenazine (13e) was identified as a promising lead compound for treating tardive dyskinesia. In this study, we separated 13e via chiral chromatography and acquired R,R,R-13e [(+)-13e] and S,S,S-13e [(−)-13e], and we investigated their VMAT2-inhibitory activity and examined the related pharmacodynamics and pharmacokinetics properties using in vitro and in vivo models (+)-13e displayed high affinity for VMAT2 (Ki = 1.48 nM) and strongly inhibited [3H]DA uptake (IC50 = 6.11 nM) in striatal synaptosomes. Conversely, its enantiomer was inactive. In vivo, (+)-13e decreased locomotion in rats in a dose-dependent manner. The treatment had faster, stronger, and longer-lasting effects than valbenazine at an equivalent dose. Mono-oxidation was the main metabolic pathway in the liver microsomes and in dog plasma after oral administration, and glucuronide conjugation of mono-oxidized and/or demethylated products and direct glucuronide conjugation were also major metabolic pathways in dog plasma. O-detrifluoroethylation of (+)-13e did not occur. Furthermore, CYP3A4 was identified as the primary isoenzyme responsible for mono-oxidation and demethylation metabolism, and CYP2C8 was a secondary isoenzyme (+)-13e displayed high permeability across the Caco-2 cell monolayer, and it was not a P-glycoprotein substrate as demonstrated by its high oral absolute bioavailability (75.9%) in dogs. Thus, our study findings highlighted the potential efficacy and safety of (+)-13e in the treatment of tardive dyskinesia. These results should promote its clinical development.

scholarly journals In vivo imaging of vesicular monoamine transporter 2 in pancreas using an 18F epoxide derivative of tetrabenazine

2008 ◽  
Vol 35 (8) ◽  
pp. 825-837 ◽  
Author(s):  
Hank F. Kung ◽  
Brian P. Lieberman ◽  
Zhi-Ping Zhuang ◽  
Shunichi Oya ◽  
Mei-Ping Kung ◽  
...  
Keyword(s):  
In Vivo Imaging ◽  
Vesicular Monoamine Transporter ◽  
Monoamine Transporter ◽  
Vesicular Monoamine Transporter 2

scholarly journals Another Imaginary World: The ICER Claims for the Long-Term Cost-Effectiveness and Pricing of Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors in Tardive Dyskinesia

2017 ◽  
Vol 8 (4) ◽  
pp. 12
Author(s):  
Paul C. Langley
Keyword(s):  
Tardive Dyskinesia ◽  
Cost Effective ◽  
Vesicular Monoamine Transporter ◽  
Value Assessment ◽  
Monoamine Transporter ◽  
Imaginary World ◽  
Vesicular Monoamine Transporter 2 ◽  
Product Pricing

The recently released value assessment of vesicular monoamine transporter 2 (VMAT2) inhibitors in tardive dyskinesia by the Institute for Clinical and Economic Review (ICER) relies upon a long-term modeling exercise to support recommendations for what the ICER sees as the appropriate pricing for these products if prices are to be judged ‘cost-effective’. In this case, the recommendations are for a substantive price reduction of some 90% over WAC. Needless to say, this recommendation is unlikely to be welcomed with open arms by the respective manufacturers of valbenazine and deutetrabenazine. Unfortunately, as has been argued in a number of commentaries published over the past 18 months in INNOVATIONS in Pharmacy, the ICER endorsed health technology assessment methodology that underpins this exercise in building a modeled imaginary world to justify product pricing recommendations is fatally flawed: it does not meet the standards of normal science. Rather than addressing the issue of claims validation for VMAT2 products, the question of generating modeled evaluable claims, among others, for clinical, quality of life and resource utilization outcomes, the analysis focuses on claims that are neither credible nor evaluable and, of course, non-replicable. A more positive and useful approach would be for ICER to focus on a framework where claims could be assessed in the short term to provide feedback to health system decision makers, physicians and patients. Instead, we are asked to believe that we can model 20 or 30 years into the future to establish non-evaluable claims for pricing and, ultimately, access. Conflict of Interest: None   Type: Commentary

scholarly journals In Vivo Evidence for Low Striatal Vesicular Monoamine Transporter 2 (VMAT2) Availability in Cocaine Abusers

2012 ◽  
Vol 169 (1) ◽  
pp. 55-63 ◽  
Author(s):  
Rajesh Narendran ◽  
Brian J. Lopresti ◽  
Diana Martinez ◽  
Neale Scott Mason ◽  
Michael Himes ◽  
...  
Keyword(s):  
Vesicular Monoamine Transporter ◽  
Monoamine Transporter ◽  
Vesicular Monoamine Transporter 2

Valbenazine and deutetrabenazine: Vesicular monoamine transporter 2 inhibitors for tardive dyskinesia

2020 ◽  
Vol 77 (3) ◽  
pp. 167-174
Author(s):  
Farah Khorassani ◽  
Kiranjit Luther ◽  
Om Talreja
Keyword(s):  
Tardive Dyskinesia ◽  
Involuntary Movement ◽  
Current Evidence ◽  
Vesicular Monoamine Transporter ◽  
Controlled Trials ◽  
Monoamine Transporter ◽  
Double Blind ◽  
Vesicular Monoamine Transporter 2 ◽  
Mesh Terms ◽  
Agent Selection

Abstract Purpose The purpose of this review is to summarize the current evidence for valbenazine and deutetrabenazine use for the treatment of tardive dyskinesia (TD). Summary A literature search was conducted to gather relevant data regarding the use of valbenazine and deutetrabenazine for TD management. PubMed, MEDLINE, and ClinicalTrials.gov were searched using the following keywords and MeSH terms: valbenazine, deutetrabenazine, tardive dyskinesia, VMAT2 inhibitors, and vesicular monoamine transporter 2 inhibitors. Randomized, double-blind, placebo-controlled trials and meta-analyses published in English from April 2015 to August 2019 were included. Valbenazine 40–80 mg and deutetrabenazine 12–36 mg per day have been evaluated for the treatment of TD. Abnormal Involuntary Movement Scale (AIMS) scores decline similarly (by 2–5 points) with use of either agent. AIMS response rates, defined by a 50% decline in symptoms, range from 33% to 50%. Both agents are well tolerated, with somnolence and akathisia reported most frequently (at low rates). Agent selection may be guided by manufacturer labeling recommendations for special populations and cost considerations. Conclusions Valbenazine and deutetrabenazine were demonstrated to be effective in decreasing AIMS scores and were well tolerated in randomized controlled trials. These treatments may be considered as a next-line option when traditional strategies are not feasible or are ineffective. Head-to-head studies are warranted to decipher if either agent is preferable in terms of efficacy or tolerability.

scholarly journals Comparing pharmacologic mechanism of action for the vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine in treating tardive dyskinesia: does one have advantages over the other?

CNS Spectrums ◽  
2018 ◽  
Vol 23 (4) ◽  
pp. 239-247 ◽  
Author(s):  
Stephen M. Stahl
Keyword(s):  
Tardive Dyskinesia ◽  
Mechanism Of Action ◽  
The Other ◽  
Vesicular Monoamine Transporter ◽  
Monoamine Transporter ◽  
Vesicular Monoamine Transporter 2

The two approved treatments for tardive dyskinesia both inhibit the vesicular monoamine transporter type 2 (VMAT2) yet have pharmacologic properties that distinguish one from the other. Knowing these differences may help optimize which treatment to select for individual patients.

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