Department of pharmaceutics, Centre for pharmaceutical sciences, University college of engineering, science and technology, JNTUH, Kukatpally, Hyderabad,500085
Deutetrabenazine is a recently approved therapy for the management of chorea in Huntington’s disease (HD) and represents the first deuterium-modified medication authorized by the U.S. Food and Drug Administration for clinical use. It is a vesicular monoamine transporter 2 (VMAT2) inhibitor and structurally similar to tetrabenazine, it is structurally derived from tetrabenazine, with selective substitution of deuterium atoms which prolongs its half-life and permits more stable plasma concentrations. This pharmacokinetic modification enables twice-daily dosing, up to a maximum of 48 mg per day, providing exposure comparable to higher daily doses of tetrabenazine. Deutetrabenazine demonstrated significant reductions in chorea severity. The treatment was generally well tolerated, with an adverse event profile similar to placebo. The indirect comparative analyses suggests that while both deutetrabenazine and tetrabenazine effectively reduce chorea, tetrabenazine may show a marginally greater side effects, whereas deutetrabenazine appears to have superior tolerability. However, these findings have not been confirmed in direct head-to-head trials. Overall, available data support deutetrabenazine as an effective and potentially better-tolerated option for the treatment of chorea in Huntington’s disease. Further comparative studies and long-term real-world data are needed to clarify its relative efficacy and safety profile..
Huntington’s disease (HD) is a known hereditary neurodegenerative disorder which is caused by a trinucleotide CAG repeat expansion i.e., mutation on chromosome IV in the HTT gene.HTT is responsible for producing a protein called huntingtin protein which is an essential factor for health of nerve cells in brain 1,2 .Huntington’s disease can cause motor & behavioral disturbances, cognitive dysfunction, with common symptom of being chorea.3The patients with HD are mostly suffering with chorea which can interfere with daily function and may cause injury.
Figure 1: 3D illustration of Huntington’s disease 4
As we know that from past many years, there was no drug for treatment of chorea associated with HD approved by US Food and Drug Administration, but in 2008, they approved tetrabenazine for treatment of chorea associated with HD. Tetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor which lowers the number of monoamines at the synapse.5 VMAT 2 is a transport protein Which is present across the CNS which plays a major role in placing monoamine neurotransmitters (dopamine, serotonin, norepinephrine) into presynaptic vesicles. Hence by decreasing dopamine transport into these presynaptic vesicles, leads to decrease in synaptic dopamine release, thus reducing postsynaptic dopamine D2 receptor activity.6 By studying about clinical trials performed for Huntington’s disease , tetrabenazine was found to be effective for the treatment of chorea in HD; but the side effects caused by tetrabenazine made the population to use it in limited way.3,Despite of its effectiveness, they found an increased risk of depression, suicidality, anxiety, and parkinsonism in patients treated with tetrabenazine when performed controlled trails.7 By these studies to overcome the side effect profile of tetrabenazine they formulated Deutetrabenazine which was approved by US Food and Drug Administration in 2017.Deutetrabenazine is a deuterated compound of tetrabenazine which is structurally similar.8
Deutetrabenazine is reversible inhibitor of vesicular monoamine transporter and used in treatment of chorea associated with HD, which depletes dopamine levels by inhibiting uptake into presynaptic vesicles
2.HOW DEUTERIUM IMPACTS MEDICATION:
Deuterium, a stable, harmless, naturally occurring isotope of hydrogen. At any given time, humans contain 5 g of deuterium, primarily in the form of heavy water (D2O).8 The molecule that results from replacing some hydrogen atoms with deuterium will have a comparable structure and receptor-binding characteristics, but its kinetics will be very different. The half-life is extended because it takes eight times as much energy to break a carbon–deuterium covalent bond as a carbon–hydrogen link. Dopamine, serotonin, and norepinephrine are monoamine neurotransmitters that are placed into presynaptic vesicles. By decreasing dopamine transport into these presynaptic vesicles, synaptic dopamine release is lessened, thus reducing dyskinetic movement severity and postsynaptic dopamine D2 receptor activation.9,10
3.SYNTHESIS OF TETRABENAZINE AND DEUTETRABENAZINE:
Tetrabenazine which is initially developed as an antipsychotic drug invented by Hoffmann-La-Roche (Nutley, NJ, USA) 15 Nitoman, and Xenazine are other names of tetrabenazine. It is a benzoquinolizine derivative with the chemical name 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[α]quinolizin-2-one.
Figure 3: Structures of tetrabenazine and deutetrabenazine 18
Deutetrabenazine is a nonradioactive analogue of tetrabenazine, where the 6 hydrogen atoms of 9&10 methoxy (−OCH3) substituents are replaced with deuterium atoms. The original developer of deutetrabenazine was Auspex Pharmaceuticals, located in La Jolla, California, USA. After purchasing Auspex Pharmaceuticals in 2015, Teva filed a new drug application (NDA) in the US to treat Huntington's disease. The FDA approved the first deuterated medication, deutetrabenazine, for Teva Pharmaceutical's marketing on April 3, 2017, to treat chorea linked to Huntington's disease.15 In order to prepare tetrabenazine, Hoffmann-La-Roche described a method that involves condensing 6,7-dimethoxy3,4-dihydroisoquinoline with 3-methylene-5-methyl-2-hexanone in an alkaline medium. According to a new technology disclosed by the Wellcome Foundation (London, U.K.).3,4-dihydro-6,7-dimethoxyisoquinoline reacted with (2-acetyl-4-methylpentyl) trimethylammonium iodide in alcohol to produce tetrabenazine. Benefits of this approach include a notably greater yield (65%), less solvent consumption, and the elimination of the need for mercuric acetate. 17
Auspex Pharmaceuticals created a method for creating Deutetrabenazine by reacting 2-acetyl-4-methylpentyl) trimethylammonium iodide with 6,7-dimethoxy-3,4-dihydroisoquinoline-d6 in ethanol. Column chromatography was used to isolate the product in a 35% yield. The Low yields were obtained by this method, which used genotoxic iodomethane-d3 and the laborious column chromatography approach.19 As a result, industry could not use it. In a different method, Auspex Pharmaceuticals explained how to prepare deutetrabenazine by reacting 2-acetyl-4methylpentyl) trimethylammonium iodide with 6,7-dimethoxy-3,4-dihydroisoquinoline-d6 hydrochloride in methanol-water. Iodomethane-d3.8, which is costly and genotoxic, was also used in this method. Following oral administration, deutetrabenazine is rapidly and extensively metabolized to the primary circulating active metabolite (3), which is subsequently further broken down by CYP2D6 to produce 10-O-desmethyl metabolite (4) and 9-
Odesmethyl metabolite (5).18,19
Figure 4: Metabolism of deutetrabenazine
Figure5: Improved synthesis of tetrabenazine (1) and deutetrabenazine (2)
{Note: Reagents and conditions: (a) MeOH−H2O, K2CO3, IPA; (b) TPP, DIAD, MeOH; (c) TPP, DIAD, MeOHd4.} The synthesis of 1 and 2 start with same starting material, 6,7-dihydroxy-3,4-dihydroisoquinoline (6), which was treated with (2-acetyl-4-methylpentyl)trimethylammonium iodide (7) or 3-methylene-5-methyl-2-hexanone (8) in the solvent methanol-water and potassium carbonate is used as a base at required temperature of 65−70 °C to obtain an intermediate (9) of >98.5% purity with HPLC purity.17 To obtain tetrabenazine in 96% of yield the intermediate 9 was then reacted with solvent methanol. (or) treated with MeOH-d4 to get deutetrabenazine as a product in 92% yield by using Mitsunobu reaction conditions.16,18
4.BRAND NAME OF DEUTETRABENAZINE
AUSTEDO® XR, AUSTEDO®
5.PHARMACOKINETICS:
The liver thoroughly breaks down deutetrabenazine into two active metabolites: beta-dihydrotetrabenazine & alpha-dihydrotetrabenazine. Peak plasma concentrations (Cmax) of deuterated active metabolites are obtained about 3–4 hours after oral administration, when at least 80% of deutetrabenazine is absorbed. It is advised that deutetrabenazine be taken with food because it increases Cmax by 50% when taken with food during administration. Deutetrabenazine has a half-life of nine to ten hours, and CYP2D6 is the primary metabolizer of its active metabolites prior to renal excretion. When compared with an equal oral dose of tetrabenazine, the half-life of deutetrabenazine was increased twofold (measured by active metabolites alpha- and beta-HTBZ concentrations in plasma).11
6.MECHANISM OF ACTION OF DEUTETRABENAZINE:
Deutetrabenazine works by blocking the VMAT2 protein, which lowers the quantity of neurotransmitter available in the nerve terminals and, as a result, lessens undesired bodily motions. In the brain, nerve cells called neurons regulate movement or motor function.
Figure 2: Mechanism of action of Deutetrabenazine12
These neurons communicate with one another by sending chemical messengers called neurotransmitters from one nerve cell to another. This system may be compromised in movement disorders including tardive dyskinesia and Huntington's disease. The uncontrollable movements might be alleviated by reducing the quantity of chemical messengers between the nerve cells. The VMAT2 protein regulates the amount of neurotransmitter that is absorbed and retained in the nerve cell. Since VMAT2 is blocked by the VMAT2 inhibitors, there is a decreased. Because VMAT2 inhibitors block VMAT2, less neurotransmitter is accessible, which reduces undesirable bodily motions.11
7.DOSING:
A maximum dose of 48 mg/d or 36 mg/d for people using strong CYP2D6 inhibitors or who are 2D6 poor metabolizers is advised for deutetrabenazine. The suggested starting dosage is 6 mg twice daily taken with food, increasing by 6 mg/d weekly as needed. Patients with hepatic impairment should not use deutetrabenazine. Patients with renal impairment do not have any data. It has not been determined whether dosages greater than 48 mg/d are both effective and tolerable. Acute dystonia, oculogyric crisis, nausea and vomiting, sweating, drowsiness, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor have all been linked to tetrabenazine overdoses ranging from 100 to 1,000 mg, according to published reports.12
8.CONTRAINDICATIONS:
Patients on reserpine, tetrabenazine, valbenazine, or MAOIs, as well as those with hepatic impairment, should not take deutetrabenazine for TD. The usage of deutetrabenazine in pregnant women is unknown, as is the case with most drugs; nevertheless, oral administration of deutetrabenazine (5, 10, or 30 mg/kg/d) or tetrabenazine (30 mg/kg/d) to pregnant rats throughout organogenesis had no discernible impact on embryofetal development. On a body surface area (mg/m2) basis, the greatest dose tested was six times the maximum recommended human dose of 48 mg/d. No information regarding the existence of deutetrabenazine is available.13
9. ADVERSE REACTIONS: These are the serious side effects of deutetrabenazine. It may lead to depression and suicidality in Patients with Huntington’s disease Prolongation, , Agitation, and Restlessness, Parkinsonism, Sedation & Hyperprolactinemia 21
10. DRUG INTERACTIONS:
CONCLUSION
Deutetrabenazine represents an important advancement in the management of chorea associated with Huntington’s disease. As the first FDA-approved deuterated medication, it demonstrates how deuterium modification can enhance pharmacokinetic stability, allowing for less frequent dosing and potentially improved tolerability. Current clinical evidence indicates that deutetrabenazine provides meaningful reductions in chorea severity, with an overall adverse effect profile comparable to placebo. Although both tetrabenazine and deutetrabenazine have shown statistically significant improvements in chorea compared with placebo, deutetrabenazine appears to offer advantages in tolerability. While tetrabenazine may demonstrate a slightly greater magnitude of symptomatic improvement in some analyses, its side effect burden is generally higher. Further real-world studies are needed to confirm the favorable safety profile observed in clinical trials and to better define deutetrabenazine’s place in therapy. Overall, available evidence supports deutetrabenazine as an effective and well-tolerated treatment option for chorea in Huntington’s disease, with promising advantages that warrant continued investigation.
REFERENCES
CNS Spectr. 2016;21(S1):13-24
CNS Spectr. 2016;21(S1):13-24
Adavelli Rishitha, Dr. M. Sunitha Reddy, Dr. K. Anie Vijetha, Deutetrabenazine -A Review., Int. J. of Pharm. Sci., 2026, Vol 4, Issue 3, 640-647. https://doi.org/10.5281/zenodo.18898154
10.5281/zenodo.18898154
