From the FDA Drug Label
- 2 Pharmacodynamics Cardiac Electrophysiology At the maximum recommended dose, AUSTEDO XR and AUSTEDO do not prolong the QT interval to any clinically relevant extent An exposure-response analysis on QTc prolongation from a study in extensive or intermediate (EM) and poor CYP2D6 metabolizers (PM) showed that a clinically-relevant effect can be excluded at exposures following single doses of 24 and 48 mg of AUSTEDO. Melanin Binding Deutetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, 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 pharmacodynamics of deutetrabenazine include:
- Cardiac Electrophysiology: Deutetrabenazine does not prolong the QT interval to any clinically relevant extent at the maximum recommended dose.
- Melanin Binding: Deutetrabenazine or its metabolites bind to melanin-containing tissues. Deutetrabenazine's pharmacodynamic effects are believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals 1.
From the Research
Deutetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor that works by reducing the amount of dopamine available in the brain, primarily through its metabolites, with [-]-α-deuHTBZ being the most abundant but a relatively weak VMAT2 inhibitor, and [+]-β-deuHTBZ being the most potent VMAT2 inhibitor among its metabolites 2.
Mechanism of Action
The drug functions by binding to VMAT2, which normally packages monoamines like dopamine into vesicles for release at nerve terminals. By inhibiting this transporter, deutetrabenazine decreases the uptake of monoamines into synaptic vesicles, resulting in less dopamine being available for release into the synapse. This mechanism helps control involuntary movements in conditions like Huntington's disease chorea and tardive dyskinesia.
Pharmacodynamic Profile
The pharmacodynamic profile of deutetrabenazine is characterized by its deuterated form, which strengthens certain chemical bonds, allowing for slower metabolism, longer half-life, and more consistent blood levels compared to tetrabenazine. This enables twice-daily dosing rather than more frequent administration.
Clinical Implications
Common side effects include sedation, depression, and parkinsonism due to its dopamine-depleting effects. Patients should be monitored for these effects, particularly when initiating treatment or adjusting doses, as the clinical response is directly related to the degree of VMAT2 inhibition achieved. The choice between deutetrabenazine and other VMAT2 inhibitors like valbenazine may depend on factors such as dosing frequency, titration requirements, and potential drug-drug interactions 3, 4, 5.
Recent Findings
Recent studies have further elucidated the mechanisms of VMAT2 inhibitors, including deutetrabenazine, suggesting that they may influence tardive dyskinesia through the dopaminergic synapse signaling pathway, with unique and overlapping targets compared to other treatments like vitamin E 6.