Peringatan Keamanan

Adverse reactions associated with overdosage include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor FDA Label. In case of an overdose, general supportive and symptomatic measures are recommended while monitoring cardiac rhythm and vital signs. In managing overdosage, the possibility of multiple drug involvement should always be considered FDA Label.

No carcinogenicity studies were performed with deutetrabenazine. In p53+/– transgenic mice, there were no detectable tumors following oral administration of deutetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks FDA Label. Findings from in vitro assays and in vivo mice micronucleus assay suggest that deutetrabenazine and its metabolites are unlikely to be mutagenic FDA Label. The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of tetrabenazine had no effects on mating and reproductive systems of male and female rats FDA Label.

Deutetrabenazine

DB12161

small molecule approved investigational

Deskripsi

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 DB04844 A32046. 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 A32046. This allows less frequent dosing and a lower daily dose with improvement in tolerability A32043. Decreased plasma fluctuations of deutetrabenazine due to attenuated metabolism may explain a lower incidence of adverse reactions associated with deutetrabenazine A32042. Deutetrabenazine is a racemic mixture containing RR-Deutetrabenazine and SS-Deutetrabenazine FDA Label.

Huntington's disease (HD) is a hereditary, progressive neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and neuropsychiatric disturbances A32043 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 A32046. Psychomotor symptoms of HD, such as chorea, are related to hyperactive dopaminergic neurotransmission A14081. 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 A14081. 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 T28. 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 A32046. It was approved by FDA in April 2017 and is marketed under the trade name Austedo as oral tablets.

Struktur Molekul 2D

Berat 323.466
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The half-life of total (?+?)-HTBZ from deutetrabenazine is approximately 9 to 10 hours [FDA Label].
Volume Distribusi The median volume of distribution (Vc/F) of the ?-HTBZ, and the ?-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively [FDA Label]. Human PET-scans of tetrabenazine indicate rapid distribution to the brain, with the highest binding in the striatum and lowest binding in the cortex [FDA Label]. Similar distribution pattern is expected for deutetrabenazine.
Klirens (Clearance) In patients with Huntington's disease, the median clearance values (CL/F) of the ?-HTBZ, and the ?-HTBZ metabolites of deutetrabenazine are approximately 47 L/hour and 70 L/hour, respectively [FDA Label].

Absorpsi

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) FDA Label. Cmax of deuterated ?-HTBZ and ?-HTBZ are reached within 3-4 hours post-dosing FDA Label. Food may increase the Cmax of ?-HTBZ or ?-HTBZ by approximately 50%, but is unlikely to have an effect on the AUC FDA Label.

Metabolisme

Deutetrabenazine undergoes extensive hepatic biotransformation mediated by carbonyl reductase to form its major active metabolites, ?-HTBZ and ?­-HTBZ. These metabolites may subsequently metabolized to form several minor metabolites, with major contribution of CYP2D6 and minor contributions of CYP1A2 and CYP3A4/5 FDA Label.

Rute Eliminasi

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 FDA Label. Sulfate and glucuronide conjugates of the ?-HTBZ and ?-HTBZ, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine FDA Label. ?-HTBZ and ?-HTBZ metabolites accounted for less than 10% of the administered dose in the urine FDA Label.

Interaksi Makanan

2 Data
  • 1. Avoid alcohol. Additive sedative effects may occur from co-administration of deutetrabenazine with alcohol.
  • 2. Take with food. Taking deutetrabenazine with food increases its Cmax.

Interaksi Obat

1497 Data
Moricizine The risk or severity of adverse effects can be increased when Moricizine is combined with Deutetrabenazine.
Alimemazine The risk or severity of adverse effects can be increased when Alimemazine is combined with Deutetrabenazine.
Lithium cation The risk or severity of adverse effects can be increased when Lithium cation is combined with Deutetrabenazine.
Osanetant The risk or severity of adverse effects can be increased when Osanetant is combined with Deutetrabenazine.
Bifeprunox The risk or severity of adverse effects can be increased when Bifeprunox is combined with Deutetrabenazine.
BL-1020 The risk or severity of adverse effects can be increased when BL-1020 is combined with Deutetrabenazine.
Cariprazine The risk or severity of adverse effects can be increased when Cariprazine is combined with Deutetrabenazine.
Amperozide The risk or severity of adverse effects can be increased when Amperozide is combined with Deutetrabenazine.
Cyamemazine The risk or severity of adverse effects can be increased when Cyamemazine is combined with Deutetrabenazine.
Brexpiprazole The risk or severity of adverse effects can be increased when Brexpiprazole is combined with Deutetrabenazine.
Brilaroxazine The risk or severity of adverse effects can be increased when Brilaroxazine is combined with Deutetrabenazine.
Propiopromazine The risk or severity of adverse effects can be increased when Propiopromazine is combined with Deutetrabenazine.
Bromperidol The risk or severity of adverse effects can be increased when Bromperidol is combined with Deutetrabenazine.
Prothipendyl The risk or severity of adverse effects can be increased when Prothipendyl is combined with Deutetrabenazine.
Butaperazine The risk or severity of adverse effects can be increased when Butaperazine is combined with Deutetrabenazine.
Clothiapine The risk or severity of adverse effects can be increased when Clothiapine is combined with Deutetrabenazine.
Chlorproethazine The risk or severity of adverse effects can be increased when Chlorproethazine is combined with Deutetrabenazine.
Oxypertine The risk or severity of adverse effects can be increased when Oxypertine is combined with Deutetrabenazine.
Thiazinam The risk or severity of adverse effects can be increased when Thiazinam is combined with Deutetrabenazine.
Veralipride The risk or severity of adverse effects can be increased when Veralipride is combined with Deutetrabenazine.
Moperone The risk or severity of adverse effects can be increased when Moperone is combined with Deutetrabenazine.
Thiopropazate The risk or severity of adverse effects can be increased when Thiopropazate is combined with Deutetrabenazine.
Mosapramine The risk or severity of adverse effects can be increased when Mosapramine is combined with Deutetrabenazine.
Dixyrazine The risk or severity of adverse effects can be increased when Dixyrazine is combined with Deutetrabenazine.
Aripiprazole lauroxil The risk or severity of adverse effects can be increased when Aripiprazole lauroxil is combined with Deutetrabenazine.
Perphenazine enanthate The risk or severity of adverse effects can be increased when Perphenazine enanthate is combined with Deutetrabenazine.
Levosulpiride The risk or severity of adverse effects can be increased when Levosulpiride is combined with Deutetrabenazine.
Metyrosine The risk or severity of adverse effects can be increased when Metyrosine is combined with Deutetrabenazine.
Mirabegron The serum concentration of Deutetrabenazine can be increased when it is combined with Mirabegron.
Metoclopramide The risk or severity of adverse effects can be increased when Metoclopramide is combined with Deutetrabenazine.
Leuprolide The risk or severity of QTc prolongation can be increased when Leuprolide is combined with Deutetrabenazine.
Goserelin The risk or severity of QTc prolongation can be increased when Goserelin is combined with Deutetrabenazine.
Erythromycin The serum concentration of Deutetrabenazine can be increased when it is combined with Erythromycin.
Azithromycin The risk or severity of QTc prolongation can be increased when Azithromycin is combined with Deutetrabenazine.
Moxifloxacin The risk or severity of QTc prolongation can be increased when Moxifloxacin is combined with Deutetrabenazine.
Sulfisoxazole The risk or severity of QTc prolongation can be increased when Sulfisoxazole is combined with Deutetrabenazine.
Methadone The risk or severity of QTc prolongation can be increased when Methadone is combined with Deutetrabenazine.
Diltiazem The risk or severity of QTc prolongation can be increased when Diltiazem is combined with Deutetrabenazine.
Nimodipine The risk or severity of QTc prolongation can be increased when Nimodipine is combined with Deutetrabenazine.
Oxaliplatin The risk or severity of QTc prolongation can be increased when Oxaliplatin is combined with Deutetrabenazine.
Ciprofloxacin The risk or severity of QTc prolongation can be increased when Ciprofloxacin is combined with Deutetrabenazine.
Fluorouracil The risk or severity of QTc prolongation can be increased when Fluorouracil is combined with Deutetrabenazine.
Perflutren The risk or severity of QTc prolongation can be increased when Perflutren is combined with Deutetrabenazine.
Cinnarizine The risk or severity of QTc prolongation can be increased when Cinnarizine is combined with Deutetrabenazine.
Atropine The risk or severity of QTc prolongation can be increased when Atropine is combined with Deutetrabenazine.
Adenosine The risk or severity of QTc prolongation can be increased when Adenosine is combined with Deutetrabenazine.
Pentamidine The risk or severity of QTc prolongation can be increased when Pentamidine is combined with Deutetrabenazine.
Gadobenic acid The risk or severity of QTc prolongation can be increased when Gadobenic acid is combined with Deutetrabenazine.
Carbinoxamine The risk or severity of QTc prolongation can be increased when Carbinoxamine is combined with Deutetrabenazine.
Dolasetron The risk or severity of QTc prolongation can be increased when Dolasetron is combined with Deutetrabenazine.
Roxithromycin The risk or severity of QTc prolongation can be increased when Roxithromycin is combined with Deutetrabenazine.
Nalidixic acid The risk or severity of QTc prolongation can be increased when Nalidixic acid is combined with Deutetrabenazine.
Cinoxacin The risk or severity of QTc prolongation can be increased when Cinoxacin is combined with Deutetrabenazine.
Granisetron The risk or severity of QTc prolongation can be increased when Granisetron is combined with Deutetrabenazine.
Ondansetron The risk or severity of QTc prolongation can be increased when Ondansetron is combined with Deutetrabenazine.
Levosimendan The risk or severity of QTc prolongation can be increased when Levosimendan is combined with Deutetrabenazine.
Desloratadine The risk or severity of QTc prolongation can be increased when Desloratadine is combined with Deutetrabenazine.
Lomefloxacin The risk or severity of QTc prolongation can be increased when Lomefloxacin is combined with Deutetrabenazine.
Dimenhydrinate The risk or severity of QTc prolongation can be increased when Dimenhydrinate is combined with Deutetrabenazine.
Papaverine The risk or severity of QTc prolongation can be increased when Papaverine is combined with Deutetrabenazine.
Chlorpheniramine The risk or severity of QTc prolongation can be increased when Chlorpheniramine is combined with Deutetrabenazine.
Nifedipine The risk or severity of QTc prolongation can be increased when Nifedipine is combined with Deutetrabenazine.
Levofloxacin The risk or severity of QTc prolongation can be increased when Levofloxacin is combined with Deutetrabenazine.
Gemifloxacin The risk or severity of QTc prolongation can be increased when Gemifloxacin is combined with Deutetrabenazine.
Ofloxacin The risk or severity of QTc prolongation can be increased when Ofloxacin is combined with Deutetrabenazine.
Mibefradil The risk or severity of QTc prolongation can be increased when Mibefradil is combined with Deutetrabenazine.
Probucol The risk or severity of QTc prolongation can be increased when Probucol is combined with Deutetrabenazine.
Terlipressin The risk or severity of QTc prolongation can be increased when Terlipressin is combined with Deutetrabenazine.
Prenylamine The risk or severity of QTc prolongation can be increased when Prenylamine is combined with Deutetrabenazine.
Lofexidine The risk or severity of QTc prolongation can be increased when Lofexidine is combined with Deutetrabenazine.
Azimilide The risk or severity of QTc prolongation can be increased when Azimilide is combined with Deutetrabenazine.
Pracinostat The risk or severity of QTc prolongation can be increased when Pracinostat is combined with Deutetrabenazine.
Technetium Tc-99m ciprofloxacin The risk or severity of QTc prolongation can be increased when Technetium Tc-99m ciprofloxacin is combined with Deutetrabenazine.
Garenoxacin The risk or severity of QTc prolongation can be increased when Garenoxacin is combined with Deutetrabenazine.
Tedisamil The risk or severity of QTc prolongation can be increased when Tedisamil is combined with Deutetrabenazine.
Tucidinostat The risk or severity of QTc prolongation can be increased when Tucidinostat is combined with Deutetrabenazine.
Telavancin The risk or severity of QTc prolongation can be increased when Telavancin is combined with Deutetrabenazine.
Pazopanib The risk or severity of QTc prolongation can be increased when Pazopanib is combined with Deutetrabenazine.
Nemonoxacin The risk or severity of QTc prolongation can be increased when Nemonoxacin is combined with Deutetrabenazine.
Nilvadipine The risk or severity of QTc prolongation can be increased when Nilvadipine is combined with Deutetrabenazine.
Antazoline The risk or severity of QTc prolongation can be increased when Antazoline is combined with Deutetrabenazine.
Bedaquiline The risk or severity of QTc prolongation can be increased when Deutetrabenazine is combined with Bedaquiline.
Fendiline The risk or severity of QTc prolongation can be increased when Fendiline is combined with Deutetrabenazine.
Eperisone The risk or severity of QTc prolongation can be increased when Eperisone is combined with Deutetrabenazine.
Butriptyline The risk or severity of QTc prolongation can be increased when Butriptyline is combined with Deutetrabenazine.
Ceritinib The risk or severity of QTc prolongation can be increased when Ceritinib is combined with Deutetrabenazine.
Lenvatinib The risk or severity of QTc prolongation can be increased when Lenvatinib is combined with Deutetrabenazine.
Benidipine The risk or severity of QTc prolongation can be increased when Benidipine is combined with Deutetrabenazine.
Dexchlorpheniramine maleate The risk or severity of QTc prolongation can be increased when Dexchlorpheniramine maleate is combined with Deutetrabenazine.
Amifampridine The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Deutetrabenazine.
Mocetinostat The risk or severity of QTc prolongation can be increased when Mocetinostat is combined with Deutetrabenazine.
Entinostat The risk or severity of QTc prolongation can be increased when Entinostat is combined with Deutetrabenazine.
Gilteritinib The risk or severity of QTc prolongation can be increased when Gilteritinib is combined with Deutetrabenazine.
CUDC-101 The risk or severity of QTc prolongation can be increased when CUDC-101 is combined with Deutetrabenazine.
Simendan The risk or severity of QTc prolongation can be increased when Simendan is combined with Deutetrabenazine.
Ricolinostat The risk or severity of QTc prolongation can be increased when Ricolinostat is combined with Deutetrabenazine.
Mizolastine The risk or severity of QTc prolongation can be increased when Mizolastine is combined with Deutetrabenazine.
Abexinostat The risk or severity of QTc prolongation can be increased when Abexinostat is combined with Deutetrabenazine.
Oxatomide The risk or severity of QTc prolongation can be increased when Oxatomide is combined with Deutetrabenazine.
Sitafloxacin The risk or severity of QTc prolongation can be increased when Sitafloxacin is combined with Deutetrabenazine.

Target Protein

Synaptic vesicular amine transporter SLC18A2

Referensi & Sumber

Artikel (PubMed)
  • PMID: 28387387
    Paton DM: Deutetrabenazine: Treatment of hyperkinetic aspects of Huntington's disease, tardive dyskinesia and Tourette syndrome. Drugs Today (Barc). 2017 Feb;53(2):89-102. doi: 10.1358/dot.2017.53.2.2589164.
  • PMID: 28920068
    Rodrigues FB, Duarte GS, Costa J, Ferreira JJ, Wild EJ: Tetrabenazine Versus Deutetrabenazine for Huntington's Disease: Twins or Distant Cousins? Mov Disord Clin Pract. 2017 Jul-Aug;4(4):582-585. doi: 10.1002/mdc3.12483. Epub 2017 Mar 29.
  • PMID: 28668671
    Anderson KE, Stamler D, Davis MD, Factor SA, Hauser RA, Isojarvi J, Jarskog LF, Jimenez-Shahed J, Kumar R, McEvoy JP, Ochudlo S, Ondo WG, Fernandez HH: Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017 Aug;4(8):595-604. doi: 10.1016/S2215-0366(17)30236-5. Epub 2017 Jun 28.
  • PMID: 28446646
    Fernandez HH, Factor SA, Hauser RA, Jimenez-Shahed J, Ondo WG, Jarskog LF, Meltzer HY, Woods SW, Bega D, LeDoux MS, Shprecher DR, Davis C, Davis MD, Stamler D, Anderson KE: Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study. Neurology. 2017 May 23;88(21):2003-2010. doi: 10.1212/WNL.0000000000003960. Epub 2017 Apr 26.
  • PMID: 27380342
    Frank S, Testa CM, Stamler D, Kayson E, Davis C, Edmondson MC, Kinel S, Leavitt B, Oakes D, O'Neill C, Vaughan C, Goldstein J, Herzog M, Snively V, Whaley J, Wong C, Suter G, Jankovic J, Jimenez-Shahed J, Hunter C, Claassen DO, Roman OC, Sung V, Smith J, Janicki S, Clouse R, Saint-Hilaire M, Hohler A, Turpin D, James RC, Rodriguez R, Rizer K, Anderson KE, Heller H, Carlson A, Criswell S, Racette BA, Revilla FJ, Nucifora F Jr, Margolis RL, Ong M, Mendis T, Mendis N, Singer C, Quesada M, Paulsen JS, Brashers-Krug T, Miller A, Kerr J, Dubinsky RM, Gray C, Factor SA, Sperin E, Molho E, Eglow M, Evans S, Kumar R, Reeves C, Samii A, Chouinard S, Beland M, Scott BL, Hickey PT, Esmail S, Fung WL, Gibbons C, Qi L, Colcher A, Hackmyer C, McGarry A, Klos K, Gudesblatt M, Fafard L, Graffitti L, Schneider DP, Dhall R, Wojcieszek JM, LaFaver K, Duker A, Neefus E, Wilson-Perez H, Shprecher D, Wall P, Blindauer KA, Wheeler L, Boyd JT, Houston E, Farbman ES, Agarwal P, Eberly SW, Watts A, Tariot PN, Feigin A, Evans S, Beck C, Orme C, Edicola J, Christopher E: Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial. JAMA. 2016 Jul 5;316(1):40-50. doi: 10.1001/jama.2016.8655.
  • PMID: 20135628
    Wimalasena K: Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry. Med Res Rev. 2011 Jul;31(4):483-519. doi: 10.1002/med.20187. Epub 2010 Feb 4.
Textbook
  • ISBN: 978-0-7020-3471-8
    39. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 489-490). Edinburgh: Elsevier/Churchill Livingstone.

Contoh Produk & Brand

Produk: 27 • International brands: 0
Produk
  • Austedo
    Tablet, coated • 6 mg/1 • Oral • US • Approved
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    Kit; Tablet • 6 mg/1 • Oral • US • Approved
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    Kit; Tablet • - • Oral • US • Approved
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  • Austedo
    Kit; Tablet, coated • - • Oral • US • Approved
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Menampilkan 8 dari 27 produk.

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