Treatment of Chorea Associated with Huntington's Disease: Focus on Tetrabenazine

Setter, Stephen M.; Neumiller, Joshua J.; Dobbins, Erin K.; Wood, Lindy; Clark, Jeffrey; DuVall, Cristina A.K.; Santiago, Anthony

doi:10.4140/tcp.n.2009.524

Cited by 24 publications

(11 citation statements)

References 44 publications

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“…Six subjects in the PM cohort discontinued following the 72 mg dose due to treatment‐related anxiety. Anxiety as an AE of deutetrabenazine and the other vesicular monoamine transporter 2 inhibitors, tetrabenazine and valbenazine, has been previously reported 15,28 …”

Section: Discussionmentioning

confidence: 83%

“…Anxiety as an AE of deutetrabenazine and the other vesicular monoamine transporter 2 inhibitors, tetrabenazine and valbenazine, has been previously reported. 15,28 In conclusion, the study described in this report enabled a thorough examination of the exposure levels for the parent drug and the deuterated α-HTBZ and β-HTBZ metabolites in subjects who were classified as either CYP2D6 EMs or PMs. This allowed us to determine the potential effect of each deuterated metabolite on the risk of QT prolongation in each cohort and create a model that included both populations with different ratios of the active metabolites.…”

Section: Discussionmentioning

confidence: 93%

“…This was demonstrated in a drug-drug interaction study in which the magnitude of the effect of paroxetine, a time-dependent irreversible inhibitor of CYP2D6, 12 on the metabolism of deuterated αand β-HTBZ after administration of deutetrabenazine was less than that previously observed for tetrabenazine. 13,14 In a randomized, double-blind, placebo-and positive-controlled crossover study in healthy subjects, tetrabenazine, at a single dose of 50 mg, caused an ≈8-millisecond mean increase in a measure of cardiac repolarization, the QT interval corrected for heart rate (QTc) 15 (90%CI, 5.0-10.4 milliseconds). Subsequently, the effect of both tetrabenazine and deutetrabenazine on cardiac repolarization was examined in a randomized, double-blind, placebo-and positive-controlled (moxifloxacin 400 mg) crossover QT/QTc study that evaluated changes in QT prolongation following administration of single doses of tetrabenazine 50 mg in comparison with 12-and 24-mg single doses of deutetrabenazine.…”

mentioning

confidence: 99%

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Evaluation of Deutetrabenazine's Potential to Delay Cardiac Repolarization Using Concentration‐QTc Analysis

Schneider

Darpö

Loupe

et al. 2022

Clinical Pharm in Drug Dev

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Deutetrabenazine (Austedo) is indicated in adults for chorea associated with Huntington disease and tardive dyskinesia. Escalating deutetrabenazine doses were administered to healthy volunteers who were cytochrome P450 2D6 extensive/intermediate metabolizers (EMs) or poor metabolizers (PMs) to determine pharmacokinetic exposure of parent drug and active metabolites (α-dihydrotetrabenazine [α-HTBZ] and β-dihydrotetrabenazine [β-HTBZ]), and collect corresponding electrocardiograms (ECGs) for evaluation of the cardiodynamic effect using concentration-QTc (C-QTc) modeling. Participants (12 EMs, 24 PMs) received placebo or single doses of deutetrabenazine (24, 48, and 72 mg) to achieve plasma concentrations exceeding therapeutic range in both cohorts. Pharmacokinetic samples were obtained over 72 hours after dosing and were time matched with 12-lead ECGs extracted from continuous ECG recordings. C-QTc analysis, using linear mixed-effects modeling and model selection procedure, characterized the relationship between plasma concentrations of deutetrabenazine, deuterated α-HTBZ and β-HTBZ, and the change from baseline in QT interval corrected using Fridericia's formula. Deutetrabenazine exhibited linear kinetics, and a C-QTc model with deuterated α-HTBZ and β-HTBZ was selected to best describe the C-QTc relationship in pooled EM and PM data. This model predicted a placebo-corrected Fridericia corrected QT interval prolongation higher than 10 milliseconds can be excluded at concentrations associated with the maximum recommended doses in both populations. Adverse events increased with higher exposure as reflected by the higher event number in the PM cohort receiving 48 and 72 mg doses. No subject discontinued due to cardiac-related adverse events and no clinically relevant ECG findings were reported. Thus, this study found that deutetrabenazine does not have a clinically relevant effect on QT prolongation at maximum recommended doses in either cytochrome P450 2D6 EMs or PMs.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

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Evaluation of Deutetrabenazine's Potential to Delay Cardiac Repolarization Using Concentration‐QTc Analysis

Schneider

Darpö

Loupe

et al. 2022

Clinical Pharm in Drug Dev

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“…For this patient, thyroid function testing should be performed annually, and when hypothyroidism is discovered, thyroid hormone replacement therapy should be initiated. For choreoathetosis, Tetrabenazine and Levodopa therapy have been reported to effectively reduce chorea (Setter et al, 2009;Rosati et al, 2015).…”

Section: Clinical Impact Of Genetic Diagnosesmentioning

confidence: 99%

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders

Guo

et al. 2020

Front. Genet.

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Background: Both whole exome sequencing and copy number variants sequencing were applied to identify the genetic cause of rare pediatric disorders. In our study, we aimed to investigate the diagnostic yield of parallel tests of trio whole exome sequencing and copy number variants sequencing and its clinical utility. Methods: After collecting detailed clinical information, a total of 60 patients were referred to parallel tests of whole exome sequencing and copy number variants sequencing, which used shared initial libraries. Results: 26 pathogenic or likely pathogenic single nucleotide variants and 11 copy number variants were identified in 32 patients. 65.4% (17/26) of the SNVs were novel. The overall diagnosis rate was 53.3%. For the patients with positive results, 22 (36.7%) patients were diagnosed by whole exome sequencing and 10 (16.7%) patients were diagnosed by copy number variants sequencing. We also reviewed clinical impact on selected cases. Conclusion: We adopted an approach by performing parallel tests of trio whole exome sequencing and copy number variants sequencing with shared initial libraries. This strategy is relatively efficient and cost-effective for the diagnosis of rare pediatric disorders with high heterogeneity.

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“…[4][5] Tetrabenazine and Deutetrabenazine are the only drugs that have been approved by the US FDA for treatment of chorea related to HD but it has their limitations like drug interaction and side effects. [6][7][8] 3 nitro propionic acid (3-NP) induced rat model of HD is found to be the most suitable preclinical model. 9 It is a mycotoxin, at chronic administration (10 mg/kg/day, 3-6 weeks) induces some features similar to those displayed by HD patients.…”

mentioning

confidence: 99%

Silymarin, Quercetin and Hesperidin Combination Ameliorates Learning and Memory Deficit in 3 Nitro Propionic Acid Induced Rat Model of Huntington’s Disease

Bhimanwar¹,

Ghaisas²,

Shete³

2022

IJPI

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Huntington's disease is a very uncommon, neurological disease diagnosed by chorea (abnormal involuntary movements), behavioural manifestations, psychological behavioral symptoms, and cognitive impairment, which develop at the age of 30-50 years, and severity increases with age. 1-2 Worldwide prevalence ranges from 5.96 to 13.7 per 100,000. 3 The exact pathogenic mechanism underlying HD has not been explained yet but mitochondrial dysfunction, excitotoxicity, neuroinflammation, oxidative stress, neurochemical imbalance, and apoptosis are the most well-accepted mechanisms. [4][5] Tetrabenazine and Deutetrabenazine are the only drugs that have been approved by the US FDA for treatment of chorea related to HD but it has their limitations like drug interaction and side effects. [6][7][8] 3 nitro propionic acid (3-NP) induced rat model of HD is found to be the most suitable preclinical model. 9 It is a mycotoxin, at chronic administration (10 mg/kg/day, 3-6 weeks) induces some features similar to those displayed by HD patients. The 3-NP model can mimic and reproduce the hyperkinetic and hypokinetic symptoms of HD, depending on the time and dose administered, thus allowing the initial and late phases of HD to be evaluated. [10][11][12] Bioflavonoids belong to a group of natural substances with variable phenolic structures and exhibit a variety of activities including antioxidant, anti-inflammatory, antiallergic, antiviral, and anticarcinogenic properties. [13][14] While there have only been a few studies on the potential beneficial effects of flavonoids in HD models, the published results suggest specific flavonoids could be of potential clinical use against HD. 15 Silymarin, a flavonolignan from the seeds of milk thistle (Silybum marianum), is a mixture of mainly three flavonolignans, which are silidianin, and silychristine, silybin and here silybin is considered to be more active. 16 Silymarin significantly inhibits the LPS (lipopolysaccharide)-induced activation of microglia and the production of inflammatory mediators, such as tumour necrosis factoralpha and nitric oxide (NO), and reduced the damage to dopaminergic neurons and protects the neurons of SNC (substantia nigra pars compacta). [17][18] Quercetin is categorized as a flavonol, prominently found in variety of fruits and vegetables. 19 Quercetin reverses 3-NP induced inhibition of respiratory chain complexes, restores ATP level, attenuates mitochondrial oxidative stress in terms of lipid peroxidation, and prevents mitochondrial swelling. Long-term treatment with quercetin can safely and effectively improve selected elements of motor performance and increase muscle mass during initial phases of aging. 20 Hesperidin, a bioflavonoid, is an abundant and inexpensive by-product of 'Citrus cultivation' with abundant of pharmacological properties and medicinal uses. 21 Hesperidin inhibits elevation of TNF-α level, apoptosis, and excitotoxicity in a quinolinic acid-induced rat model of HD. 22 The role of hesperidin concentration of 100 mg/kg p.o. on reduction of MDA (...

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Treatment of Chorea Associated with Huntington's Disease: Focus on Tetrabenazine

Abstract: HD is often accompanied by chorea, and the treatment with TBZ in this patient population often results in decreased chorea. Pharmacists managing patients on TBZ need to be well versed in TBZ's potential side effects, drug interactions, and unique dosing considerations.

Cited by 24 publications

References 44 publications

Evaluation of Deutetrabenazine's Potential to Delay Cardiac Repolarization Using Concentration‐QTc Analysis

Evaluation of Deutetrabenazine's Potential to Delay Cardiac Repolarization Using Concentration‐QTc Analysis

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders

Silymarin, Quercetin and Hesperidin Combination Ameliorates Learning and Memory Deficit in 3 Nitro Propionic Acid Induced Rat Model of Huntington’s Disease

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