Mechanism of action and PK profile

MOA

VMAT2 inhibition can help regulate dopamine function1

Some vesicular monoamine transporter 2 (VMAT2) inhibitors reduce available dopamine via alpha and/or beta metabolites that block sequestration in the presynaptic vesicle.2

  • Unsequestered dopamine is degraded by monoamine oxidase3
  • Reducing dopamine levels in the presynaptic neuron results in less dopamine signaling to the postsynaptic neuron, leading to fewer abnormal involuntary movements1

The precise mechanism by which AUSTEDO (deutetrabenazine) tablets exerts its effects in the treatment of tardive dyskinesia (TD) and chorea associated with Huntington’s disease (HD) is unknown, but it is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals.2

  • The major circulating active metabolites (alpha-dihydrotetrabenazine [HTBZ] and beta-HTBZ) of deutetrabenazine are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into presynaptic vesicles and depletion of monoamine stores
  • VMAT2 is inhibited through both the alpha and beta metabolites to provide potent inhibition
Presynaptic neuron: AUSTEDO® (deutetrabenazine) tablets, VMAT2, vesicle. Postsynaptic neuron: monoamines (e.g. dopamine). Increased VMAT2 Inhibition leads to decreased dopamine.

See how the VMAT2 inhibition of AUSTEDO reduces dopamine levels

View the results of AUSTEDO clinical trials in patients with TD or patients with chorea associated with HD.

Flexible treatment options that effectively inhibit VMAT2 may help address the dopamine dysregulation that can lead to TD4,5

PK PROFILE

A differentiated PK profile

AUSTEDO features deuterium, extending the half-life of active therapeutic metabolites to 9-10 hours2,6

  • Pharmacokinetic (PK) simulations of area under the curve (AUC)-matched exposure to active metabolites based on dosing regimens of AUSTEDO (9 mg twice daily) and tetrabenazine (12.5 mg 3 times a day) at steady state.7

Plasma Concentrations of Alpha and Beta Metabolites Over 24 Hours—PK Model7

Plasma Concentrations of Alpha and Beta Metabolites Over 24 hours-PK Model. 3 Peaks = Tetrabenazine 3 times a day vs. 2 Peaks = AUSTEDO® (deutetrabenazine) tablets twice daily. The correlation between plasma levels and clinical efficacy has not been established.

Slower rate of rise, lower peak-to-trough fluctuations, and reduced Cmax may allow for reduced interpatient metabolic variability.6,7

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Learn more about why AUSTEDO may be right for the diverse treatment needs of your patients.
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References: 1. Solmi M, Pigato G, Kane JM, Correll CU. Treatment of tardive dyskinesia with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:1215–1238. doi:10.2147/DDDT.S133205 2. AUSTEDO® (deutetrabenazine) tablets current Prescribing Information Parsippany, NJ. Teva Neuroscience, Inc. 3. Blakely RD, Edwards RH. Vesicular and plasma membrane transporters for neurotransmitters. Cold Spring Harb Perspect Biol. 2012;4(2):a005595. doi:10.1101/cshperspect.a005595 4. Zai CC, Tiwari AK, Mazzoco M, et al. Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia. J Psychiatr Res. 2013;47(11):1760-1765. Published online September 6, 2013. doi:10.1016/j.jpsychires.2013.07.025 5. Aquino CC, Lang AE. Tardive dyskinesia syndromes: current concepts. Parkinsonism Relat Disord. 2014;20(suppl 1):S113-117. doi: 10.1016/S1353-8020(13)70028-2 6. Tung R. The development of deuterium-containing drugs. Innovations in Pharmaceutical Technology. 2010;32(32):24-28. 7. Data on file. Parsippany, NJ: Teva Neuroscience, Inc.