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General Description:

Deutetrabenazine, identified by CAS number 1392826-25-3, is a notable compound with significant therapeutic applications. Deutetrabenazine is a novel, highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the management of chorea associated with Huntington’s disease. It is a hexahydro-dimethoxybenzoquinolizine derivative and a deuterated . The presence of deuterium in deutetrabenazine increases the half-lives of the active metabolite and prolongs their pharmacological activity by attenuating CYP2D6 metabolism of the compound . This allows less frequent dosing and a lower daily dose with improvement in tolerability . Decreased plasma fluctuations of deutetrabenazine due to attenuated metabolism may explain a lower incidence of adverse reactions associated with deutetrabenazine . Deutetrabenazine is a racemic mixture containing RR-Deutetrabenazine and SS-Deutetrabenazine . Huntington's disease (HD) is a hereditary, progressive neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and neuropsychiatric disturbances that interfere with daily functioning and significantly reduce the quality of life. The most prominent physical symptom of HD that may increase the risk of injury is chorea, which is an involuntary, sudden movement that can affect any muscle and flow randomly across body regions . Psychomotor symptoms of HD, such as chorea, are related to hyperactive dopaminergic neurotransmission . Deutetrabenazine depletes the levels of presynaptic dopamine by blocking VMAT2, which is responsible for the uptake of dopamine into synaptic vesicles in monoaminergic neurons and exocytotic release . As with other agents for the treatment of neurodegenerative diseases, deutetrabenazine is a drug to alleviate the motor symptoms of HD and is not proposed to halt the progression of the disease . In clinical trials of patients with HD, 12 weeks of treatment of deutetrabenazine resulted in overall improvement in mean total maximal chorea scores and motor signs than placebo . It was approved by FDA in April 2017 and is marketed under the trade name Austedo as oral tablets.

Indications:

This drug is primarily indicated for: Deutetrabenazine is indicated in adults patients for the treatment of tardive dyskinesia and for chorea associated with Huntington's disease. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Deutetrabenazine undergoes metabolic processing primarily in: 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 . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Deutetrabenazine are crucial for its therapeutic efficacy: 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 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Deutetrabenazine is an important consideration for its dosing schedule: The half-life of total (α+β)-HTBZ from deutetrabenazine is approximately 9 to 10 hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Deutetrabenazine exhibits a strong affinity for binding with plasma proteins: 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. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Deutetrabenazine from the body primarily occurs through: 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 . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Deutetrabenazine is distributed throughout the body with a volume of distribution of: 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. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Deutetrabenazine is a critical factor in determining its safe and effective dosage: 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 . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Deutetrabenazine exerts its therapeutic effects through: 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 . 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 . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Deutetrabenazine functions by: 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 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Deutetrabenazine belongs to the class of organic compounds known as tetrahydroisoquinolines. These are tetrahydrogenated isoquinoline derivatives, classified under the direct parent group Tetrahydroisoquinolines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Tetrahydroisoquinolines class, specifically within the None subclass.

Categories:

Deutetrabenazine is categorized under the following therapeutic classes: Cytochrome P-450 CYP1A2 Substrates, Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 Substrates, Drugs that are Mainly Renally Excreted, Heterocyclic Compounds, Fused-Ring, Highest Risk QTc-Prolonging Agents, Nervous System, QTc Prolonging Agents, Quinolizines, Vesicular Monoamine Transporter 2 Inhibitor, Vesicular Monoamine Transporter 2 Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.