Tetrabenazine

Tetrabenazine is a VMAT-inhibitor used for treatment of hyperkinetic movement disorder. Target: Others tetrabenazine (TBZ), a monoamine-depleting and a dopamine-receptor-blocking drug. TBZ is an effective and safe drug for the treatment of a variety of hyperkinetic movement disorders. In contrast to typical neuroleptics, TBZ has not been demonstrated to cause tardive dyskinesia [1, 2]. Twenty patients with tardive dyskinesia (mean duration = 43.7 months) were videotaped before and after tetrabenazine treatment. One patient did not tolerate tetrabenazine owing to sedation. The remaining 19 were rated after a mean of 20.3 weeks at a mean tetrabenazine dose of 57.9 mg/day. There were significant improvements in mean scores on both the patient AIMS self-rating and the AIMS motor subset evaluated by the blind videotape raters. All 19 patients continued to take tetrabenazine after the study [3].

References:
[1]. Jankovic, J. and J. Beach, Long-term effects of tetrabenazine in hyperkinetic movement disorders. Neurology, 1997. 48(2): p. 358-62. [2]. Kenney, C., C. Hunter, and J. Jankovic, Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Mov Disord, 2007. 22(2): p. 193-7. [3]. Ondo, W.G., P.A. Hanna, and J. Jankovic, Tetrabenazine treatment for tardive dyskinesia: assessment by randomized videotape protocol. Am J Psychiatry, 1999. 156(8): p. 1279-81.

Tetrabenazine: Spotlight on Drug Review.[Pubmed:27721587]

Ann Neurosci. 2016 Sep;23(3):176-185.

BACKGROUND: Tetrabenazine (TBZ) is the only US Food and Drug Administration-approved drug for the treatment of chorea related to Huntington's disease and other hyperkinetic disorders. TBZ was first synthesized in 1950, and was then used for the treatment of psychosis. But later its potential in treating hyperkinetic disorders was proved by its ability to block vesicular monoamine transporters 2 and deplete monoamine stores. There is still lack of awareness about the therapeutic potential of this drug. SUMMARY: TBZ had been approved only for the treatment of chorea, but several clinical studies have been conducted by different research groups and it was concluded that TBZ is effective in various other conditions such as tardive dyskinesia, dystonia, tics, and Tourette's syndrome, thus, highlighting the need for further clinical trials in these conditions. KEY MESSAGE: The intention of this review is to sum up the information regarding chemistry, mechanism of action, pharmacokinetics, interactions, contraindications, adverse effects, and clinical efficacy of TBZ in diseases other than Huntington's chorea.

Indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease.[Pubmed:28265459]

J Clin Mov Disord. 2017 Mar 1;4:3.

BACKGROUND: Vesicular monoamine transporter 2 (VMAT2) inhibitors can improve hyperkinetic movements, and are effective treatment options for chorea of Huntington disease (HD). Tetrabenazine was assessed for treating chorea in the TETRA-HD trial, and while efficacious, there are tolerability concerns possibly due to its pharmacokinetic properties. DeuTetrabenazine is a novel VMAT2 inhibitor that contains deuterium, which extends active metabolite half-lives and minimizes drug concentration fluctuations. In the First-HD trial, deuTetrabenazine was efficacious in treating chorea and was generally well tolerated. In the absence of a head-to-head trial, we performed an indirect treatment comparison (ITC) of the tolerability of deuTetrabenazine and Tetrabenazine for the treatment of HD-associated chorea, as observed in the First-HD and TETRA-HD trials, using well-established comparison methods. METHODS: Data from the Phase III, 12-week, parallel-group, clinical trials First-HD (N = 90) and TETRA-HD (N = 84) were used to conduct an ITC of the tolerability of deuTetrabenazine versus Tetrabenazine using two anchor-based methods: Bucher comparison for unadjusted ITCs, and matching indirect comparison for adjusted ITCs. Overall adverse events (AEs; mild, moderate, and severe), serious AEs, specific AEs occurring in >/=10% of patients, and discontinuations (all-cause and AE-related) were included in the analysis. The risk differences of these outcomes for deuTetrabenazine and Tetrabenazine were estimated by subtracting the applicable placebo-adjusted risk in First-HD from that of TETRA-HD. Sensitivity analyses were performed to address differences between trials, and p-values were obtained from z-tests. RESULTS: Compared with Tetrabenazine, deuTetrabenazine was associated with a significantly lower risk of moderate to severe AEs and neuropsychiatric AEs including agitation, akathisia, depression, depression/agitated depression, drowsiness/somnolence, insomnia, and parkinsonism in both adjusted and unadjusted analyses (p < 0.05 for each). DeuTetrabenazine had a significantly lower rate of dose reduction or dose reduction/suspension in the unadjusted and adjusted analyses (p < 0.001 for each). DeuTetrabenazine resulted in numerically more mild AEs, such as diarrhea and coughing; however, these results were not statistically significant. CONCLUSIONS: This indirect treatment comparison demonstrates that for the treatment of HD chorea, deuTetrabenazine has a favorable tolerability profile compared to Tetrabenazine. TRIAL REGISTRATION: ClinicalTrials.gov NCT01795859 and NCT00219804.

Orodispersible films based on amorphous solid dispersions of tetrabenazine.[Pubmed:28007543]

Int J Pharm. 2017 Feb 25;518(1-2):242-252.

In this work, the formation and stability of amorphous solid dispersions (SDs) as orodispersible films (ODF) were investigated using Tetrabenazine (TBZ) as a poorly water soluble drug. The influence of polymer nature and pH-modifier incorporation to form and maintain SDs was investigated. TBZ-loaded ODF were formulated using 4 different polymers (HPMC, PVP, Pullulan, and HEC). Binary systems (BS) were obtained mixing the drug with different polymers, while ternary (TS) systems were also obtained by adding citric acid to solubilize TBZ in the mixture. Drug dissolution studies, thermal analysis and X-ray diffraction were carried out to characterize the physical state of API in ODF. ODF made of TS allowed a major improvement of TBZ dissolution profile in buccal conditions compared to a pure drug or BS. DSC and X-ray diffraction revealed that API was in amorphous state in TS while remained crystalline in BS. Following 6 months of storage, TBZ recrystallization occurred for PVP-TS and HEC-TS which induced a decrease of drug release in saliva conditions. HPMC and PUL-TS maintained API in amorphous state during 6 months. Briefly, amorphous SDs were obtained by the pre-dissolution of the drug in acidified water and incorporation in polymeric films. The miscibility and potential interaction between TBZ and polymers have been identified as important factor to explain stability differences.

Formulation of orodispersible films for paediatric therapy: investigation of feasibility and stability for tetrabenazine as drug model.[Pubmed:27671542]

J Pharm Pharmacol. 2017 May;69(5):582-592.

OBJECTIVES: Orodispersible films (ODF) were formulated to facilitate Tetrabenazine (TBZ) administration to paediatric population for the treatment of hyperkinetic movement disorders. METHODS: ODF were obtained by solvent casting/evaporation method using four different polymers (HPMC, PVP, pullulan and HEC). Physicochemical, mechanical and biopharmaceutical characterizations as well as API state in ODF by thermal analysis were investigated to define and compare formulations. ODF stability was also monitored during 6 months to follow evolution of properties. KEY FINDINGS: Analyses at T0 showed few differences between formulations: results of physicochemical and mechanical characterizations were almost similar for each formulation and TBZ appeared at the amorphous state in all cases. ODF delivery system allowed a major improvement of TBZ dissolution profile in buccal conditions compared with pure drug. However, after 3 and 6 months of stability, a TBZ recrystallization occurred for formulations based on PVP and HEC associated with a decrease of drug release in saliva conditions. CONCLUSIONS: HPMC-ODF (F1) appeared as the best formulation. Indeed, physicochemical, mechanical and biopharmaceutical characteristic remained intact. In addition, TBZ remained in amorphous state during stability study.

Chimeric vesicular monoamine transporters identify structural domains that influence substrate affinity and sensitivity to tetrabenazine.[Pubmed:8621690]

J Biol Chem. 1996 Feb 9;271(6):2979-86.

The vesicular monoamine transporters (VMATs) 1 and 2 show close sequence similarity but substantial differences in apparent substrate affinity and drug sensitivity. To identify structural domains that determine these functional characteristics, chimeric transporters were constructed and their properties were analyzed in a heterologous expression system. The results implicate multiple regions in the recognition of serotonin and histamine and the sensitivity to Tetrabenazine. Two domains of VMAT2, one extending from transmembrane domain (TMD) 5 to the beginning of TMD8 and the other from the end of TMD9 through TMD12, increase the affinity for serotonin and histamine as well as the sensitivity to Tetrabenazine but only in the context of more C-terminal and more N-terminal VMAT2 sequences, respectively. In addition, the extreme N terminus of VMAT2 alone suffices to confer a partial increase in substrate affinity and Tetrabenazine sensitivity. Despite these similarities among the interactions with serotonin, histamine, and Tetrabenazine, the region of VMAT2 from TMD3 through TMD4 increases serotonin affinity but not histamine affinity or Tetrabenazine sensitivity, and whereas the region from TMD5 to TMD8 of VMAT2 increases serotonin affinity in the context of more C-terminal VMAT2 sequences, the region encompassing TMD5 through TMD7 reduces serotonin but not histamine affinity or Tetrabenazine sensitivity in the context of more N-terminal VMAT2 sequences. Thus, the chimeric analysis also reveals differences between serotonin recognition and the recognition of both histamine and Tetrabenazine that may account for the observed differences in their interaction with the transport protein.

Tetrabenazine-induced depletion of brain monoamines: characterization and interaction with selected antidepressants.[Pubmed:6489435]

Eur J Pharmacol. 1984 Jul 20;102(3-4):425-30.

The peripheral administration of Tetrabenazine (TBZ) induces rapid depletion of brain regional concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT). With respect to both dosage and time, striatal DA was most sensitive to the effects of TBZ while hypothalamic NE was least affected. Pretreatment with the monoamine oxidase (MAO)-inhibitor, clorgyline (1-6 mg/kg) dose-dependently prevented the reduction of all three monoamines for up to 60 min after TBZ (3 mg/kg). The TBZ-induced depletion of cortical NE was also significantly antagonized by desmethylimipramine (DMI) but was of shorter duration (up to 30 min after TBZ). DMI, however, did not influence the effect of TBZ on striatal DA or hypothalamic 5-HT. The protective effects of both clorgyline and DMI were also evident under the conditions of the behavioral TBZ test utilizing high doses of TBZ (20 mg/kg).

Tetrabenazine, an amine-depleting drug, also blocks dopamine receptors in rat brain.[Pubmed:6864517]

J Pharmacol Exp Ther. 1983 Jun;225(3):515-21.

Tetrabenazine (TBZ) is used in the treatment of hyperkinetic movement disorders. Its effect is thought to be mediated by depletion of dopamine (DA) stores. We studied other possible mechanisms of action of this drug. TBZ decreased DA concentration in rat striatum and nucleus accumbens in a dose-dependent manner with an IC50 of approximately 1.2 mg.kg-1. Maximal depletion was obtained within 30 min with only partial recovery at 8 hr. TBZ induced (at 40 mg . kg-1) 5- to 8-fold increases in 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations in both brain regions. Unlike reserpine, TBZ completely abolished the apomorphine-induced inhibition of DA synthesis under conditions in which this effect is mediated by presynaptic DA receptors. Both TBZ (5 mg . kg-1) and reserpine (5 mg . kg-1) depleted, at 1 hr, striatal DA content by approximately 90%. However, TBZ, but not reserpine, significantly stimulated in vivo tyrosine hydroxylase activity. TBZ also inhibited [3H]spiperone binding in the striatum with Ki = 2.1 X 10(-6) M. In rats, with unilateral destruction of the nigrostriatal pathway with 6-hydroxydopamine, pretreatment with TBZ significantly reduced the number of rotations induced by apomorphine. Finally, in rats treated with either TBZ (5 mg . kg-1) or reserpine (5 mg . kg-1), prolactin levels significantly increased as compared to control values. TBZ, but not reserpine, blocked apomorphine inhibition of prolactin secretion. We conclude that, in addition to depleting monoamines, TBZ also blocks both presynaptic and postsynaptic DA receptors in rat brain.