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Deutetrabenazine | CAS No: 1392826-25-3 | GMP-certified suppliers
A medication that treats chorea in Huntington's disease and tardive dyskinesia by reducing involuntary movements in adult patients.
Therapeutic categories
Cytochrome P-450 CYP1A2 SubstratesCytochrome P-450 CYP2D6 SubstratesCytochrome P-450 CYP3A SubstratesCytochrome P-450 CYP3A4 SubstratesCytochrome P-450 CYP3A5 SubstratesCytochrome P-450 Substrates
Generic name
Deutetrabenazine
Molecule type
small molecule
CAS number
1392826-25-3
DrugBank ID
DB12161
Approval status
Approved drug, Investigational drug
ATC code
N07XX16
Primary indications
- Deutetrabenazine is indicated in adults patients for the treatment of tardive dyskinesia and for chorea associated with Huntington's disease
Product Snapshot
- Deutetrabenazine is formulated as oral tablets, including film-coated and extended-release forms
- It is primarily utilized for the treatment of tardive dyskinesia and chorea associated with Huntington's disease in adults
- The product has received approval for use in the US and holds both approved and investigational statuses
Clinical Overview
Deutetrabenazine (CAS number 1392826-25-3) is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of chorea associated with Huntington's disease (HD) and tardive dyskinesia in adult patients. HD is a progressive neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and neuropsychiatric symptoms. Chorea, an involuntary, erratic movement, is a prominent motor symptom linked to hyperactive dopaminergic neurotransmission. Deutetrabenazine acts by reversibly inhibiting VMAT2, which reduces presynaptic uptake and storage of monoamines including dopamine, serotonin, norepinephrine, and histamine, leading to depletion of their synaptic levels and amelioration of hyperkinetic movements.
Deutetrabenazine is a deuterated hexahydro-dimethoxybenzoquinolizine derivative. The incorporation of deuterium atoms attenuates metabolism primarily through CYP2D6 by creating stronger carbon-deuterium bonds compared to carbon-hydrogen bonds, resulting in prolonged half-lives of the active metabolites (α- and β-dihydrotetrabenazine) and sustained pharmacological effects with reduced plasma concentration fluctuations. This pharmacokinetic profile supports less frequent dosing and potentially improved tolerability relative to non-deuterated analogs.
Absorption and metabolism include CYP2D6, CYP3A4, and others within the cytochrome P450 family, with renal excretion being a primary elimination route. Following oral administration, active metabolites account for the clinical activity. Deutetrabenazine demonstrates binding affinity to melanin-containing tissues and has shown minor QTc interval prolongation at therapeutic single doses; however, higher exposure effects have not been comprehensively studied.
Safety considerations include monitoring for depression, suicidality, and QTc prolongation due to its central nervous system activity and pharmacodynamic profile. The drug does not alter the progression of HD but alleviates chorea symptomatology. Deutetrabenazine is marketed under the trade name Austedo.
From an API sourcing perspective, quality control must address the stereochemical complexity since deutetrabenazine is a racemic mixture containing RR- and SS-enantiomers, requiring stringent chiral purity assessment. Additionally, control of deuterium incorporation at key molecular sites is critical to ensure consistent pharmacokinetic and safety profiles. Stability, impurity profiling, and compliance with regulatory manufacturing standards for deuterated compounds should be prioritized in procurement processes.
Deutetrabenazine is a deuterated hexahydro-dimethoxybenzoquinolizine derivative. The incorporation of deuterium atoms attenuates metabolism primarily through CYP2D6 by creating stronger carbon-deuterium bonds compared to carbon-hydrogen bonds, resulting in prolonged half-lives of the active metabolites (α- and β-dihydrotetrabenazine) and sustained pharmacological effects with reduced plasma concentration fluctuations. This pharmacokinetic profile supports less frequent dosing and potentially improved tolerability relative to non-deuterated analogs.
Absorption and metabolism include CYP2D6, CYP3A4, and others within the cytochrome P450 family, with renal excretion being a primary elimination route. Following oral administration, active metabolites account for the clinical activity. Deutetrabenazine demonstrates binding affinity to melanin-containing tissues and has shown minor QTc interval prolongation at therapeutic single doses; however, higher exposure effects have not been comprehensively studied.
Safety considerations include monitoring for depression, suicidality, and QTc prolongation due to its central nervous system activity and pharmacodynamic profile. The drug does not alter the progression of HD but alleviates chorea symptomatology. Deutetrabenazine is marketed under the trade name Austedo.
From an API sourcing perspective, quality control must address the stereochemical complexity since deutetrabenazine is a racemic mixture containing RR- and SS-enantiomers, requiring stringent chiral purity assessment. Additionally, control of deuterium incorporation at key molecular sites is critical to ensure consistent pharmacokinetic and safety profiles. Stability, impurity profiling, and compliance with regulatory manufacturing standards for deuterated compounds should be prioritized in procurement processes.
Identification & chemistry
| Generic name | Deutetrabenazine |
|---|---|
| Molecule type | Small molecule |
| CAS | 1392826-25-3 |
| UNII | P341G6W9NB |
| DrugBank ID | DB12161 |
Pharmacology
| Summary | Deutetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor that reduces synaptic monoamine uptake and depletes dopamine, serotonin, norepinephrine, and histamine stores in nerve terminals. Its active metabolites reversibly inhibit VMAT2, leading to modulation of involuntary movement symptoms in conditions such as tardive dyskinesia and Huntington’s disease chorea. The molecule’s deuterium substitution slows metabolic degradation without altering its pharmacodynamic activity. |
|---|---|
| Mechanism of action | The precise mechanism of action of deutetrabenazine in mediating its anti-chorea effects is not fully elucidated. Deutetrabenazine reversibly depletes the levels of monoamines, such as dopamine, serotonin, norepinephrine, and histamine, from nerve terminals via its active metabolites. The major circulating metabolites are α-dihydrotetrabenazine [HTBZ] and β-HTBZ that act as reversible inhibitors of VMAT2. Inhibition of VMAT2 results in decreased uptake of monoamines into synaptic terminal and depletion of monoamine stores from nerve terminals. Deutetrabenazine contains the molecule deuterium, which is a naturally-occurring, nontoxic hydrogen isotope but with an increased mass relative to hydrogen . Placed at key positions, deuterium forms a stronger hydrogen bond with carbon that requires more energy for cleavage, thus attenuating CYP2D6-mediated metabolism without having any effect on the therapeutic target . |
| Pharmacodynamics | In clinical trials, there was an evidence of clinical effectiveness of deutetrabenazine in improving the symptoms of involuntary movements in patient with tardive dyskinesia by reducing the mean Abnormal Involuntary Movement Scale (AIMS) score [A32044, A32045]. In a randomized, double-blind, placebo-controlled crossover study in healthy male and female subjects, single dose administration of 24 mg deutetrabenazine results in an approximately 4.5 msec mean increase in QTc. Effects at higher exposures to deutetrabenazine or its metabolites have not been evaluated. Deutetrabenazine and its metabolites were shown to bind to melanin-containing tissues including eyes, skin and fur in pigmented rats. After a single oral dose of radiolabeled deutetrabenazine, radioactivity was still detected in eye and fur at 35 days following dosing. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Synaptic vesicular amine transporter | Humans | inhibitor |
ADME / PK
| Absorption | The extent of absorption is 80% with oral deutetrabenazine. As deutetrabenazine is extensively metabolized to its main active metabolites following administration, linear dose dependence of peak plasma concentrations (Cmax) and AUC was observed for the metabolites after single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). Cmax of deuterated α-HTBZ and β-HTBZ are reached within 3-4 hours post-dosing. Food may increase the Cmax of α-HTBZ or β-HTBZ by approximately 50%, but is unlikely to have an effect on the AUC. |
|---|---|
| Half-life | The half-life of total (α+β)-HTBZ from deutetrabenazine is approximately 9 to 10 hours. |
| Protein binding | At doses ranging from 50 to 200 ng/mL _in vitro_, tetrabenazine protein binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%. Similar protein binding pattern is expected for deutetrabenazine and its metabolites. |
| Metabolism | Deutetrabenazine undergoes extensive hepatic biotransformation mediated by carbonyl reductase to form its major active metabolites, α-HTBZ and β-HTBZ. These metabolites may subsequently metabolized to form several minor metabolites, with major contribution of CYP2D6 and minor contributions of CYP1A2 and CYP3A4/5. |
| Route of elimination | Deutetrabenazine is mainly excreted in the urine as metabolites. In healthy subjects, about 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Sulfate and glucuronide conjugates of the α-HTBZ and β-HTBZ, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine. α-HTBZ and β-HTBZ metabolites accounted for less than 10% of the administered dose in the urine. |
| Volume of distribution | The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively. Human PET-scans of tetrabenazine indicate rapid distribution to the brain, with the highest binding in the striatum and lowest binding in the cortex. Similar distribution pattern is expected for deutetrabenazine. |
| Clearance | In patients with Huntington's disease, the median clearance values (CL/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 47 L/hour and 70 L/hour, respectively. |
Formulation & handling
- Deutetrabenazine is a small molecule drug formulated exclusively for oral administration in tablet form.
- The compound exhibits moderate lipophilicity (LogP 3.4) and low water solubility, which may influence formulation strategies.
- Administration with food is recommended to enhance absorption, and concomitant use with alcohol should be avoided due to additive sedative effects.
Regulatory status
| Lifecycle | The API is currently under patent protection in the United States with key patents expiring between 2031 and 2034, indicating it is in the mid to late stages of its patent lifecycle in this market. Generic entry and broader market competition are likely to increase following these expiry dates. |
|---|
| Markets | US |
|---|
Supply Chain
| Supply chain summary | Deutetrabenazine is primarily marketed in the US under the branded product Austedo, with manufacturing and supply dominated by originator companies holding multiple active patents valid through 2031 to 2034. The patent protection indicates limited current generic competition, with potential for increased generic entry following patent expirations in the early to mid-2030s. There is no indication of branded products marketed outside the US in this dataset. |
|---|
Safety
| Toxicity | Adverse reactions associated with overdosage include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. In case of an overdose, general supportive and symptomatic measures are recommended while monitoring cardiac rhythm and vital signs. In managing overdosage, the possibility of multiple drug involvement should always be considered. No carcinogenicity studies were performed with deutetrabenazine. In p53+/– transgenic mice, there were no detectable tumors following oral administration of deutetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks. Findings from in vitro assays and in vivo mice micronucleus assay suggest that deutetrabenazine and its metabolites are unlikely to be mutagenic. The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of tetrabenazine had no effects on mating and reproductive systems of male and female rats. |
|---|
High Level Warnings:
- Overdosage may result in acute dystonia, oculogyric crisis, and cardiovascular effects such as hypotension
- Continuous monitoring of cardiac rhythm and vital signs is advised
- In managing overdose, consider the potential involvement of multiple drugs
Deutetrabenazine is a type of Central Nervous System Agents
Central Nervous System (CNS) Agents are a crucial category of pharmaceutical Active Pharmaceutical Ingredients (APIs) that specifically target the central nervous system. The CNS encompasses the brain and spinal cord, playing a vital role in regulating and controlling various bodily functions, including cognition, movement, emotions, and sensory perception. These agents are designed to interact with specific receptors, enzymes, or ion channels within the CNS to modulate neural activity and restore normal functioning.
CNS agents comprise a diverse range of pharmaceutical APIs, including analgesics, anesthetics, antipsychotics, sedatives, hypnotics, anti-epileptics, and antidepressants. Each subcategory addresses distinct neurological disorders and conditions. For instance, analgesics alleviate pain by targeting receptors in the brain and spinal cord, while antipsychotics are employed to manage psychosis symptoms in mental illnesses such as schizophrenia.
The development of CNS agents involves rigorous research, molecular modeling, and extensive clinical trials to ensure safety, efficacy, and specific target engagement. Pharmaceutical companies invest significant resources in identifying novel drug targets, synthesizing new compounds, and optimizing their pharmacological properties. These agents undergo rigorous regulatory evaluations and must adhere to stringent quality standards and guidelines.
Given the prevalence of CNS disorders globally, the market demand for effective CNS agents is substantial. The development of innovative CNS APIs not only improves patient outcomes but also provides valuable commercial opportunities for pharmaceutical companies. Continued advancements in CNS agent research and development hold the promise of groundbreaking therapies that can improve the quality of life for individuals affected by neurological conditions.
