Valbenazine (NBI-98854) targets vesicular monoamine transporter 2 (VMAT2) (Kᵢ = 110-190 nM in rat striatal/rat forebrain/human platelet homogenates); its metabolite (+)-α-dihydrotetrabenazine (R,R,R-HTBZ) also targets VMAT2 (Kᵢ = 1.0-2.8 nM in rat striatal homogenates, Kᵢ = 4.2 nM in rat forebrain homogenates, Kᵢ = 2.6-3.3 nM in human platelet homogenates); another metabolite NBI-136110 targets VMAT2 (Kᵢ = 160-220 nM in rat striatal/rat forebrain/human platelet homogenates) [1]

In rat striatum and human platelets, valbenazine demonstrates VMAT2 binding affinities with Kis values of 110 and 150 nM, respectively [1].

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1. Radioligand-binding studies showed that Valbenazine (NBI-98854) inhibited [³H]-HTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates with a Kᵢ value of 110-190 nM, exhibiting inhibitory activity but lower potency than its metabolite R,R,R-HTBZ [1]
2. The metabolite R,R,R-HTBZ of Valbenazine (NBI-98854) potently inhibited [³H]-HTBZ binding to VMAT2 in rat striatal homogenates (Kᵢ = 1.0-2.8 nM), rat forebrain homogenates (Kᵢ = 4.2 nM), and human platelet homogenates (Kᵢ = 2.6-3.3 nM), showing high potency for VMAT2 [1]
3. The metabolite NBI-136110 of Valbenazine (NBI-98854) inhibited [³H]-HTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates with a Kᵢ value of 160-220 nM, with lower potency than R,R,R-HTBZ [1]
4. A broad panel screen involving >80 receptor, transporter, and ion channel sites demonstrated that Valbenazine (NBI-98854), R,R,R-HTBZ, and NBI-136110 had no significant off-target interactions at serotonin (5-HT₁A, 5-HT₂A, 5-HT₂B) or dopamine (D₁ or D₂) receptor sites [1]

Oral valbenazine (10 mg/kg) causes ptosis in rats, which is mainly an adrenergic response, and raises plasma prolactin, which is primarily a dopaminergic response [1].

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1. In vivo studies in rats measuring ptosis and prolactin secretion confirmed that R,R,R-HTBZ (metabolite of Valbenazine (NBI-98854)) interacted with VMAT2 in a specific and dose-dependent manner; tetrabenazine also showed similar dose-dependent interactions with VMAT2 in these assays [1]

1. Radioligand-binding assays were performed to evaluate the inhibitory effects of Valbenazine (NBI-98854), tetrabenazine, and their metabolites on VMAT2; homogenates of rat striatum, rat forebrain, and human platelets were prepared, and [³H]-HTBZ was used as the radioligand to assess the binding inhibition ability of the test compounds; the Kᵢ values were calculated to reflect the potency of each compound for VMAT2 [1]
2. A broad panel screen was conducted to detect potential off-target interactions of Valbenazine (NBI-98854), R,R,R-HTBZ, and NBI-136110; the screen covered more than 80 receptor, transporter, and ion channel sites, including serotonin (5-HT₁A, 5-HT₂A, 5-HT₂B) and dopamine (D₁, D₂) receptors, to determine whether the compounds had non-specific binding or inhibitory effects on these targets [1]

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1. In vivo experiments were carried out on rats to evaluate the interaction of Valbenazine (NBI-98854) metabolite R,R,R-HTBZ and tetrabenazine with VMAT2; ptosis and prolactin secretion levels in rats were measured after administration of different doses of the compounds, and the dose-dependent relationship of the compounds' effects on VMAT2 was analyzed; specific details such as drug dissolution formula, administration frequency, [1]

Absorption, Distribution and Excretion
Following a single oral dose of 40 mg to 300 mg (50% to 375% of the recommended therapeutic dose), the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of valbenazine and its active metabolite ([+]-α-HTBZ) increase approximately proportionally. The time to reach maximum plasma concentration (Tmax) of valbenazine after oral administration is 0.5 to 1.0 hours. Steady-state plasma concentrations of valbenazine are reached within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. [+]-α-HTBZ is gradually generated and reaches Cmax 4 to 8 hours after valbenazine administration. Consuming a high-fat meal reduces the Cmax of valbenazine by approximately 47% and the AUC by approximately 13%. The Cmax and AUC of [+]-α-HTBZ are unaffected. Following a single oral dose of 50 mg radiolabeled C-valbenazine (approximately 63% of the recommended therapeutic dose), approximately 60% and 30% of the administered radioactive material were recovered in urine and feces, respectively. Less than 2% of the drug was excreted in urine or feces as unchanged valbenazine or [+]-α-HTBZ. The mean steady-state volume of distribution of valbenazine is 92 L. The mean total plasma systemic clearance of valbenazine is 7.2 L/hr. Metabolites/Metabolites Following oral administration of valbenazine, the active metabolite ([+]-α-HTBZ) is primarily metabolized via valine ester hydrolysis, and primarily via oxidative metabolism through CYP3A4/5, resulting in monooxygenated valbenazine and other minor metabolites. [+]-α-HTBZ appears to be partially metabolized by CYP2D6.

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Biological half-life
The half-lives of valbenazine and [+]-α-HTBZ are both 15 to 22 hours.

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1. Valbenazine (NBI-98854) is converted in vivo into two important circulating metabolites: (+)-α-dihydrotetrabenazine (R,R,R-HTBZ) and a monooxygen metabolite NBI-136110; no other detailed ADME/pharmacokinetic parameters (absorption, distribution, metabolism, excretion, half-life, oral bioavailability)[1]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the use of valbenazine in humans during lactation. Based on animal studies, the manufacturer recommends avoiding breastfeeding during valbenazine treatment and for 5 days after the last dose.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
The plasma protein binding rates of valbenazine and [+]-α-HTBZ are greater than 99% and approximately 64%, respectively.

[1]. Pharmacologic Characterization of Valbenazine (NBI-98854) and Its Metabolites. J Pharmacol Exp Ther. 2017 Jun;361(3):454-461.

Valbenazine, a metabolite of bubenazine, is currently approved for the treatment of various movement disorders, particularly tardive dyskinesia (TD) and chorea associated with Huntington's disease. Tardive dyskinesia has long been considered a side effect of anti-dopamine receptor therapy, and most treatments were ineffective before the advent of bubenazine in 2008. However, challenges in using bubenazine to treat TD include frequent dosing and safety and tolerability issues. In April 2017, valbenazine, under the brand name INGREZZA, received FDA approval, becoming the first and currently only approved drug for the treatment of TD in adults. In August 2023, valbenazine received further FDA approval for the treatment of chorea associated with Huntington's disease. This approval was based on positive results from multiple trials, including the KINECT-HD Phase III study and the ongoing KINECT-HD2 open-label extension trial. Reduction in chorea severity was observed as early as 2 weeks after starting treatment with an initial dose of 40 mg. Valbenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor. The mechanism of action of valbenazine is as an inhibitor of VMAT2. See also: Valbenazine tosylate (active ingredient). Valbenazine is indicated for the treatment of adult patients with Huntington's disease-related tardive dyskinesia and chorea. FDA label Mechanism of Action Although the exact mechanism of action of valbenazine is not fully understood, it is generally believed to be achieved through the reversible inhibition of VMAT2. VMAT2 is a transporter that regulates the uptake of monoamines from the cytoplasm to storage and release in synaptic vesicles. Pharmacodynamics Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) and has a low binding affinity for VMAT1 (Ki > 10). Valbenazine is metabolized by CYP2D6 to its active metabolite, [+]-α-dihydrotetrabenazine ([+]-α-HTBZ). [+]-α-HTBZ also has a relatively high affinity for human VMAT2 (Ki ~ 3 nM). Valbenazine and [+]-α-HTBZ have very low binding affinity for dopaminergic receptors (including D2 receptors), serotonergic receptors (including 5HT2B receptors), adrenergic receptors, histamine receptors, or muscarinic receptors (Ki > 5000 nM), thus binding less to non-target receptors and resulting in higher safety. Valbenazine may cause corrected QT interval prolongation in patients with impaired CYP2D6 metabolism or those taking potent CYP2D6 or CYP3A4 inhibitors. Exposure-response analysis of clinical data from two studies in healthy volunteers revealed that higher plasma concentrations of the active metabolite were associated with longer QT intervals. Based on this model, the mean QT interval prolongation (upper limit of the two-sided 90% confidence interval) in patients taking 60 mg or 80 mg valbenazine with increased metabolite exposure (e.g., those with weaker CYP2D6 metabolic capacity) is likely to be 9.6 (12.0) ms or 11.7 (14.7) ms, respectively, while the mean QT interval prolongation (upper limit of the two-sided 90% confidence interval) in healthy volunteers taking valbenazine is likely to be 5.3 (6.7) ms or 6.7 (8.4) ms, respectively. Vesicle monoamine transporter 2 (VMAT2) is an integrated presynaptic protein that regulates the packaging of dopamine and other monoamines from neuronal vesicles and their subsequent release into the synaptic cleft [1]. 2. Valbenazine (NBI-98854) is a novel compound that selectively inhibits VMAT2 and has been approved for the treatment of tardive dyskinesia [1]. 3. Pharmacological properties of Valbenazine (NBI-98854) (selective and potent inhibition of VMAT2 with no significant off-target interactions) and recent clinical studies [KINECT 2 (NCT01733121), KINECT 3 (NCT02274558)] [1]. The good efficacy and tolerability results are consistent with the results.
4. This study also evaluated the potency and selectivity of bubenazine and its pharmacologically active metabolites and compared them with valbenazine (NBI-98854) and its metabolites [1].

C24H38N2O4

418.57

418.283

1025504-45-3

Valbenazine tosylate;1639208-54-0

24795069

Light yellow to yellow solid powder

1.1±0.1 g/cm3

507.2±50.0 °C at 760 mmHg

260.6±30.1 °C

0.0±1.3 mmHg at 25°C

1.548

4.31

1

6

8

30

569

4

CC(C)C[C@@H]1CN2CCC3=CC(=C(C=C3[C@H]2C[C@H]1OC(=O)[C@H](C(C)C)N)OC)OC

GEJDGVNQKABXKG-CFKGEZKQSA-N

InChI=1S/C24H38N2O4/c1-14(2)9-17-13-26-8-7-16-10-21(28-5)22(29-6)11-18(16)19(26)12-20(17)30-24(27)23(25)15(3)4/h10-11,14-15,17,19-20,23H,7-9,12-13,25H2,1-6H3/t17-,19-,20-,23+/m1/s1

[(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl] (2S)-2-amino-3-methylbutanoate

Valbenazine; NBI-98854; MT-5199; NBI 98854; MT5199; NBI98854; MT 5199; trade name: Ingrezza

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.97 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)