Valbenazine (DB11915): A Comprehensive Monograph on its Pharmacology, Clinical Efficacy, and Safety Profile

Drug Identification and Physicochemical Properties

Nomenclature and Identifiers

Valbenazine is a small molecule therapeutic agent primarily marketed under the brand name Ingrezza®.[1] Developed by Neurocrine Biosciences, it is also known by its developmental codes NBI-98854 and MT-5199.[4] For unambiguous identification in scientific and regulatory databases, it is assigned the Chemical Abstracts Service (CAS) Number 1025504-45-3, DrugBank Accession Number DB11915, and a Unique Ingredient Identifier (UNII) of 54K37P50KH.[4] Further identifiers include a PubChem CID of 24795069 and a ChEMBL ID of CHEMBL2364639.[4] The proprietary name Ingrezza was conditionally accepted by the U.S. Food and Drug Administration (FDA) on August 31, 2016.[7]

Molecular Profile and Structure

The molecular formula of Valbenazine is C24​H38​N2​O4​, with an average molecular weight of approximately 418.58 g/mol.[5] Its systematic International Union of Pure and Applied Chemistry (IUPAC) name isquinolizin-2-yl] (2S)-2-amino-3-methylbutanoate, which precisely defines its complex stereochemistry and constituent functional groups.[6] The molecule's structure is represented by the Simplified Molecular Input Line Entry System (SMILES) string:

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 and the InChIKey GEJDGVNQKABXKG-CFKGEZKQSA-N.[6]

For clinical use, Valbenazine is formulated as a tosylate salt (Valbenazine Tosylate, CAS 1639208-54-0).[5] The selection of this salt form is a critical aspect of its pharmaceutical development, as it is designed to enhance the drug's stability and bioavailability compared to the free base, thereby optimizing its properties for consistent oral administration and therapeutic effect.[12] Other salt forms, such as the dihydrochloride, have been synthesized for research purposes.[5]

Physicochemical Properties

Valbenazine presents as a white to off-white crystalline powder or a light yellow to yellow solid.[5] It has a melting point above 75°C, at which it begins to decompose.[13] Its solubility profile shows it is soluble in dimethylformamide (DMF) at 30 mg/ml and dimethyl sulfoxide (DMSO) at 25 mg/ml, with slight solubility in methanol, ethanol, and chloroform.[10] The compound is hygroscopic, necessitating storage under an inert atmosphere. For long-term stability (rated at four years or more), it is recommended to be stored in a freezer at -20°C.[5]

Table 1: Physicochemical and Identification Properties of Valbenazine

Property	Value
Brand Name	Ingrezza®
Generic Name	Valbenazine
Drug Type	Small Molecule
DrugBank ID	DB11915
CAS Number	1025504-45-3 (free base)
Molecular Formula	C24​H38​N2​O4​
Molecular Weight	418.58 g/mol
IUPAC Name	quinolizin-2-yl] (2S)-2-amino-3-methylbutanoate
Appearance	White to off-white crystalline powder; Light yellow to yellow solid
Solubility	Soluble in DMF, DMSO; Slightly soluble in chloroform, methanol, ethanol
Storage	-20°C, under inert atmosphere (hygroscopic)

Pharmacology and Mechanism of Action

Primary Mechanism of Action: Selective VMAT2 Inhibition

Valbenazine is classified as a selective, reversible inhibitor of the vesicular monoamine transporter 2 (VMAT2).[2] VMAT2 is a crucial presynaptic protein embedded in the membrane of synaptic vesicles within neurons. Its primary function is to transport monoamine neurotransmitters—most notably dopamine, but also serotonin, norepinephrine, and histamine—from the neuronal cytoplasm into the vesicles for storage and subsequent release into the synaptic cleft upon neuronal firing.[12]

The therapeutic effect of Valbenazine is predicated on its ability to modulate this process. By inhibiting VMAT2, Valbenazine reduces the packaging of dopamine into vesicles. This leads to a decrease in the amount of dopamine available for release, thereby attenuating dopaminergic signaling in the brain.[4] This mechanism is particularly relevant for hyperkinetic movement disorders like tardive dyskinesia (TD) and chorea associated with Huntington's disease (HD), which are hypothesized to result from dopamine receptor hypersensitivity or other forms of dopaminergic overactivity in motor control pathways.[4]

Pharmacodynamic Profile and Receptor Selectivity

Valbenazine exhibits a highly specific pharmacodynamic profile. The parent drug itself displays a moderate binding affinity for human VMAT2, with an inhibition constant (Ki​) of approximately 150 nM.[3] However, its principal therapeutic activity is mediated by its primary active metabolite, [+]-α-dihydrotetrabenazine ([+]-α-HTBZ), which binds to VMAT2 with significantly higher affinity (

Ki​ ~3 nM).[3]

A defining characteristic of Valbenazine is its high selectivity. It demonstrates a profound preference for VMAT2 over VMAT1 (Ki​ > 10 µM), the other VMAT isoform which is primarily located in peripheral tissues.[3] This selectivity is clinically important, as it minimizes interference with peripheral monoamine systems and contributes to a more favorable safety profile compared to non-selective agents.[12] Furthermore, both Valbenazine and its active metabolite show no appreciable binding affinity (

Ki​ > 5000 nM) for a broad panel of other receptors, including dopaminergic (e.g., D2), serotonergic (e.g., 5HT2B), adrenergic, histaminergic, or muscarinic receptors.[3] This lack of off-target activity is a key advantage, as it reduces the risk of side effects commonly associated with less selective drugs, such as sedation, parkinsonism, or anticholinergic effects stemming from direct receptor antagonism.[2]

Valbenazine as a Prodrug and its Active Metabolite

Valbenazine is a prodrug, meaning it is administered in an inactive or less active form and is then converted to its primary active form within the body.[2] Chemically, it is an ester of [+]-α-dihydrotetrabenazine (also known as DTBZ or HTBZ) with the naturally occurring amino acid L-valine.[4] Following oral administration, Valbenazine undergoes rapid and extensive hydrolysis in the body, cleaving the L-valine moiety to release the active metabolite, [+]-α-HTBZ.[3] This active metabolite is responsible for the majority of the drug's therapeutic effect due to its high-affinity and selective inhibition of VMAT2.[3]

Comparative Pharmacology: The Evolution from Tetrabenazine

The development of Valbenazine represents a clear example of rational drug design aimed at improving upon a first-generation therapeutic, tetrabenazine. While tetrabenazine is also a VMAT2 inhibitor used for movement disorders, its clinical utility has been hampered by a challenging side-effect profile and a need for frequent dosing.[3] The underlying issue stems from its metabolism. Tetrabenazine is converted in the body into a mixture of active metabolites, including both alpha-HTBZ and beta-HTBZ isomers.[2] While the alpha isomer provides the desired VMAT2 inhibition, the beta isomer also acts as a D2 dopamine receptor antagonist, a property that contributes significantly to adverse effects like sedation, depression, and drug-induced parkinsonism.[2]

Recognizing this mechanistic flaw, scientists designed Valbenazine to be a purified prodrug of only the therapeutically desirable isomer. By creating an L-valine ester of the pure [+]-α-HTBZ, they engineered a molecule that, upon administration, would reliably generate the single, highly selective VMAT2-inhibiting metabolite without the confounding D2-antagonizing beta isomer.[2] This targeted approach directly results in Valbenazine's improved clinical profile: high selectivity, minimal off-target effects, and a longer half-life that permits a more convenient once-daily dosing regimen, leading to enhanced safety, tolerability, and patient adherence compared to tetrabenazine.[2]

Pharmacokinetic Profile: Absorption, Distribution, Metabolism, and Excretion (ADME)

Absorption

Following oral administration, Valbenazine is rapidly absorbed, with the time to reach maximum plasma concentration (Tmax​) for the parent drug ranging from 0.5 to 1.0 hours.[3] The absolute oral bioavailability is approximately 49%.[3] The active metabolite, [+]-α-HTBZ, is formed more gradually through hydrolysis, reaching its peak plasma concentration 4 to 8 hours after the parent drug is administered.[3] Steady-state plasma concentrations of Valbenazine are achieved within one week of initiating once-daily dosing.[3]

The presence of food has a differential impact on the pharmacokinetics of the parent drug versus its active metabolite. Ingestion of a high-fat meal decreases the maximum concentration (Cmax​) of Valbenazine by approximately 47% and its total exposure (Area Under the Curve, or AUC) by about 13%.[3] Critically, however, the same meal does not meaningfully affect the

Cmax​ or AUC of the therapeutically important active metabolite, [+]-α-HTBZ.[3] This pharmacokinetic finding provides the basis for the clinical guidance that Valbenazine can be administered with or without food, enhancing convenience for patients.[1]

Distribution

Valbenazine is extensively bound to plasma proteins, with a binding fraction greater than 99%.[3] Its active metabolite, [+]-α-HTBZ, is more moderately bound at approximately 64%.[3] The high protein binding of the parent drug can influence its distribution and potential for displacement-based drug interactions. The mean steady-state volume of distribution for Valbenazine is 92 L, indicating that the drug distributes into tissues beyond the plasma compartment.[3]

Metabolism

Valbenazine undergoes extensive metabolism through two principal pathways.[3] The first is hydrolysis of the valine ester, which releases the primary active metabolite, [+]-α-HTBZ.[3] The second is oxidative metabolism, which is carried out primarily by the cytochrome P450 enzymes CYP3A4 and CYP3A5, leading to the formation of mono-oxidized valbenazine and other minor metabolites.[3] The active metabolite, [+]-α-HTBZ, is itself further metabolized, in part by another key enzyme, CYP2D6.[3]

This dual reliance on the CYP3A4 and CYP2D6 enzyme systems is the most critical feature of Valbenazine's pharmacokinetics. It is the root cause of the majority of its clinically significant drug-drug interactions and the basis for specific dosing recommendations in certain populations. These enzyme systems are highly susceptible to inhibition or induction by other medications and are known for genetic polymorphisms (particularly CYP2D6) that can alter metabolic capacity. Consequently, any factor that modifies the activity of CYP3A4 or CYP2D6 can significantly alter the exposure to Valbenazine and its active metabolite, necessitating careful clinical management.

Excretion

The primary route of elimination for Valbenazine is through hepatic metabolism, with subsequent excretion of the metabolites. Following administration of a single radiolabeled dose, approximately 60% of the radioactivity is recovered in the urine and 30% in the feces.[3] Very little of the drug is excreted in its original form; less than 2% of the dose is recovered as unchanged Valbenazine or its active metabolite [+]-α-HTBZ in either urine or feces.[3] Both the parent drug and the active metabolite have a long elimination half-life of 15 to 22 hours.[3] This prolonged half-life is a key advantage derived from its molecular design, as it supports a convenient and effective once-daily dosing regimen.[2]

Clinical Efficacy and Approved Indications

Indication 1: Tardive Dyskinesia (TD)

Tardive dyskinesia is a persistent and often disabling hyperkinetic movement disorder characterized by involuntary, repetitive movements, typically of the face, tongue, and extremities. It is an iatrogenic condition, most commonly arising from chronic exposure to dopamine receptor blocking agents, such as first- and second-generation antipsychotics.[15] The condition can cause significant physical disability and social stigma.[20] Valbenazine is indicated for the treatment of adults with TD.[1]

The approval for this indication was primarily based on the results of the KINECT-3 (NCT02274558) trial, a pivotal Phase 3 study.[2] This was a 6-week, randomized, double-blind, placebo-controlled trial involving 234 adults with moderate to severe TD and an underlying diagnosis of schizophrenia, schizoaffective disorder, or a mood disorder.[16] Participants were randomized in a 1:1:1 ratio to receive once-daily placebo, Valbenazine 40 mg, or Valbenazine 80 mg.[16] The primary efficacy endpoint was the change from baseline to week 6 in the Abnormal Involuntary Movement Scale (AIMS) dyskinesia total score (items 1–7).[16]

A crucial element of the KINECT clinical program's success was a methodological innovation. An early Phase 2 study failed to show a clear signal, a result attributed to high inter-rater variability in AIMS scoring across different clinical sites.[22] To overcome this, the KINECT-3 trial implemented a system of blinded, centralized video rating. All AIMS assessments were video-recorded and scored by a central pair of expert neurologists who were blinded to treatment assignment and study visit, thereby reducing measurement error and enhancing the reliability of the primary endpoint data.[16]

The results of KINECT-3 were definitive. The group receiving Valbenazine 80 mg/day demonstrated a statistically significant and clinically meaningful improvement in TD severity. The least squares mean change from baseline in the AIMS score was -3.2 for the 80 mg group, compared to just -0.1 for the placebo group.[16] The 40 mg/day group also showed a reduction in AIMS score (-1.9), though this did not reach statistical significance versus placebo in the primary analysis.[16] Long-term open-label extension studies confirmed that these improvements were sustained over 48 weeks of continuous treatment.[20] However, upon discontinuation of the drug during a washout period, AIMS scores returned toward baseline, confirming that Valbenazine is a symptomatic treatment rather than a curative one.[21]

Indication 2: Chorea Associated with Huntington's Disease (HD)

Huntington's disease is an inherited, progressive neurodegenerative disorder that leads to motor, cognitive, and psychiatric decline.[21] Chorea—characterized by involuntary, brief, random, and flowing movements—is a hallmark motor feature of HD, affecting over 90% of patients at some point and causing substantial functional impairment.[26] Valbenazine is also indicated for the treatment of chorea associated with HD in adults.[1]

This approval was supported by the KINECT-HD Phase 3 trial, a randomized, double-blind, placebo-controlled study that enrolled 128 adults with HD-associated chorea.[28] The primary endpoint was the change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) score, a standard measure of chorea severity in HD.[26] The trial successfully met its primary endpoint, showing that treatment with Valbenazine resulted in a highly statistically significant improvement in chorea. The placebo-adjusted mean reduction in the TMC score was 3.2 units (

p<0.0001).[26] Notably, improvements were observed as early as two weeks into treatment, even at the initial 40 mg dose.[6] The efficacy findings were further supported by statistically significant improvements in key secondary endpoints, including the Clinical Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C), where a greater proportion of patients on Valbenazine were rated as "much improved" or "very much improved" compared to placebo.[26]

Investigational Uses

Valbenazine has been explored for other conditions. It was studied for the treatment of Tourette's syndrome, though a Phase 2a trial did not meet its endpoint, a result potentially attributable to the use of doses that were too low.[4] Additionally, a Phase 3 trial investigating Valbenazine as an adjunctive treatment for schizophrenia was terminated.[30]

Table 2: Summary of Pivotal Phase 3 Clinical Trials (KINECT-3 and KINECT-HD)

Attribute	KINECT-3	KINECT-HD
Indication	Tardive Dyskinesia (TD)	Chorea of Huntington's Disease (HD)
Patient Population	Adults with moderate/severe TD and underlying schizophrenia, schizoaffective disorder, or mood disorder	Adults with HD-associated chorea
N	234	128
Doses Studied	40 mg/day, 80 mg/day, Placebo	Dose-optimized up to 80 mg/day vs. Placebo
Duration	6 weeks (placebo-controlled phase)	12 weeks
Primary Endpoint	Change from baseline in Abnormal Involuntary Movement Scale (AIMS) total score	Change from baseline in Unified Huntington's Disease Rating Scale Total Maximal Chorea (UHDRS TMC) score
Key Result	80 mg vs. Placebo: -3.2 vs. -0.1 (significant) 40 mg vs. Placebo: -1.9 vs. -0.1 (not significant)	Valbenazine vs. Placebo: Placebo-adjusted mean reduction of 3.2 units (p<0.0001)

Dosage, Administration, and Formulations

Recommended Dosing Regimens

The dosing strategy for Valbenazine is tailored to the specific indication, balancing the need for efficacy with tolerability.

• For Tardive Dyskinesia: Treatment is initiated at a dose of 40 mg orally once daily. After one week, the dose is increased to the recommended maintenance dosage of 80 mg once daily. Depending on the individual patient's clinical response and tolerability, a lower maintenance dose of 40 mg or 60 mg once daily may be considered.[1]
• For Chorea Associated with Huntington's Disease: Treatment also begins with an initial dose of 40 mg orally once daily. The dose is then titrated upwards in 20 mg increments every two weeks to reach the recommended maintenance dosage of 80 mg once daily. As with TD, the dose can be adjusted down to 40 mg or 60 mg once daily if needed based on response and tolerability.[1]

Administration Guidelines

Valbenazine is administered orally once a day and can be taken with or without food.[1] It is available in two main formulations to accommodate patient needs.

• Ingrezza® Capsule: The standard capsule should be swallowed whole with a glass of water.[1]
• Ingrezza® Sprinkle Capsule: This formulation was developed as an alternative for patients who have difficulty swallowing (dysphagia), a common issue in the target patient populations. The sprinkle capsule can either be swallowed whole or carefully opened, with the entire contents sprinkled onto one tablespoon of soft food such as applesauce, yogurt, or pudding. The mixture must be ingested immediately without chewing or crushing the granules, and the patient should drink a glass of water afterward to ensure the full dose is taken. The sprinkle formulation should not be administered via a feeding tube.[1] The development of this formulation demonstrates a patient-centric approach, expanding access to therapy for a vulnerable subset of patients who might otherwise be unable to adhere to treatment.

Dosage Adjustments in Specific Populations

Specific dose adjustments are required for certain patient populations to account for altered drug metabolism.

• Hepatic Impairment: In patients with moderate to severe hepatic impairment (Child-Pugh score 7-15), drug clearance is reduced, leading to increased exposure. For these patients, the recommended dosage is 40 mg once daily.[2]
• Renal Impairment: No dose adjustment is necessary for patients with mild to moderate renal impairment. However, Valbenazine has not been extensively studied in severe renal impairment and its use is not recommended in this group.[2]
• Known CYP2D6 Poor Metabolizers: Individuals who are genetically poor metabolizers via the CYP2D6 enzyme pathway will have impaired clearance of the active metabolite. The recommended dosage for these patients is reduced to 40 mg once daily to prevent accumulation and potential toxicity.[19]

Available Formulations and Strengths

Both Ingrezza® capsules and Ingrezza® Sprinkle capsules are available in 40 mg, 60 mg, and 80 mg strengths.[15] The capsules are distinguished by color for safety and ease of identification: the 40 mg capsule has a white body and purple cap, the 60 mg has a dark red body and purple cap, and the 80 mg capsule is entirely purple.[19]

Comprehensive Safety and Tolerability Profile

Boxed Warning: Depression and Suicidal Ideation in Huntington's Disease

Valbenazine carries a boxed warning, the FDA's most stringent warning, regarding the risk of depression and suicidal thoughts and behavior in patients with Huntington's disease.[32] This warning arises from the understanding that VMAT2 inhibitors, by depleting central monoamines including dopamine and serotonin, can unmask or worsen depressive symptoms.[34] Patients with HD already have a significantly increased baseline risk for depression and suicidality as part of their underlying disease process.[15] Therefore, the decision to use Valbenazine in this population requires a careful balancing of the clinical need for chorea treatment against the potential psychiatric risks.[32] Clinicians must closely monitor patients for the emergence or worsening of depression, suicidal ideation, or any unusual changes in behavior. It is imperative that patients, their families, and caregivers are educated about this risk and instructed to report any concerning symptoms to the treating physician immediately.[33]

Other Key Warnings, Precautions, and Contraindications

Beyond the boxed warning, several other significant safety considerations are associated with Valbenazine.

• Hypersensitivity Reactions: Valbenazine is contraindicated in patients with a history of hypersensitivity to the drug or its components. Post-marketing reports include serious reactions such as angioedema involving the lips, tongue, and larynx, which can be life-threatening. The drug must be discontinued immediately if such a reaction occurs.[15]
• Somnolence and Sedation: The most frequently reported adverse reaction in clinical trials was somnolence.[19] Patients should be cautioned about performing activities that require mental alertness, such as driving or operating heavy machinery, until they are aware of how the medication affects them. Concomitant use of alcohol or other CNS depressants can exacerbate this effect.[33]
• QT Prolongation: Valbenazine can cause a modest, dose-dependent prolongation of the QT interval on an electrocardiogram.[4] It should be avoided in patients with congenital long QT syndrome or those with known arrhythmias associated with a prolonged QT interval. The risk is increased in patients who are poor CYP2D6 metabolizers or who are taking strong inhibitors of CYP2D6 or CYP3A4, as these conditions lead to higher plasma concentrations of the drug and its active metabolite.[3]
• Neuroleptic Malignant Syndrome (NMS): NMS is a rare but potentially fatal condition associated with drugs that alter dopaminergic neurotransmission. Symptoms include hyperthermia, severe muscle rigidity, autonomic instability, and altered mental status. If NMS is suspected, Valbenazine should be discontinued immediately.[15]
• Parkinsonism: By design, Valbenazine reduces dopaminergic activity to treat hyperkinetic movements. An extension of this pharmacologic effect can be the induction of a hypodopaminergic state, manifesting as drug-induced parkinsonism (e.g., tremor, bradykinesia, rigidity, and postural instability). Post-marketing cases have been reported. If clinically significant parkinsonism develops, dose reduction or discontinuation of Valbenazine should be considered.[1]

The overall safety profile of Valbenazine is a direct and logical consequence of its mechanism of action. The primary adverse events—somnolence, parkinsonism, and the risk of depression—are all predictable outcomes of reducing central dopamine signaling in pathways responsible for arousal, motor control, and mood regulation, respectively. This mechanistic link provides a coherent framework for anticipating, monitoring, and managing the drug's potential risks.

Adverse Reactions Profile

In placebo-controlled trials for TD, the most common adverse reaction was somnolence.[2] Other reported adverse events included anticholinergic effects (dry mouth, constipation), balance disorders/falls, headache, akathisia, nausea, and arthralgia.[2] For the treatment of HD chorea, the most common side effects were somnolence, urticaria, rash, and insomnia.[32] In general, most adverse events reported in clinical trials were mild to moderate in intensity.[24]

Table 3: Common and Serious Adverse Reactions of Valbenazine

Adverse Reaction Category	Specific Reactions
Boxed Warning (HD)	Depression, Suicidal Ideation and Behavior
Serious Warnings	Hypersensitivity (Angioedema), QT Prolongation, Neuroleptic Malignant Syndrome (NMS), Parkinsonism
Common in TD Trials	Somnolence/Sedation, Dry Mouth, Constipation, Headache, Akathisia, Balance Disorders/Falls, Nausea, Arthralgia
Common in HD Trials	Somnolence/Sedation, Urticaria, Rash, Insomnia

Use in Specific Populations

• Pregnancy and Lactation: Due to a lack of sufficient human data and findings of increased stillbirths and pup mortality in animal studies, Valbenazine may cause fetal harm and should be used during pregnancy only if the potential benefit justifies the potential risk.[2] Patients are advised not to breastfeed during treatment and for 5 days after the final dose.[15]
• Pediatric and Geriatric Use: Safety and efficacy have not been established in children.[2] In geriatric patients, no dose adjustment is required. Efficacy and safety are comparable to younger adults, although older patients may have a higher rate of discontinuation due to adverse events.[20]

Clinically Significant Drug and Disease Interactions

The clinical use of Valbenazine requires careful consideration of potential drug-drug and drug-disease interactions, primarily driven by its metabolic pathways. This is particularly salient in the target psychiatric and neurological populations, who are often on complex polypharmacy regimens. A thorough medication review is an essential prerequisite to safely prescribing Valbenazine.

Pharmacokinetic Interactions (Metabolism-Based)

Valbenazine's metabolism via CYP3A4 and its active metabolite's metabolism via CYP2D6 make it susceptible to interactions with inhibitors and inducers of these enzymes.[4]

• Strong CYP3A4 Inducers: Co-administration with strong inducers of CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) can dramatically increase the metabolism of Valbenazine, leading to significantly lower plasma concentrations and a potential loss of therapeutic effect. Concomitant use is not recommended.[19]
• Strong CYP3A4 Inhibitors: Conversely, strong inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin, ritonavir) block Valbenazine's metabolism, leading to increased exposure. When used with a strong CYP3A4 inhibitor, the Valbenazine dose should be reduced to 40 mg once daily.[19]
• Strong CYP2D6 Inhibitors: Strong inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, bupropion, quinidine) reduce the clearance of the active metabolite, [+]-α-HTBZ, increasing its exposure. When used with a strong CYP2D6 inhibitor, the Valbenazine dose should also be reduced to 40 mg once daily.[19]

Pharmacodynamic Interactions

• Monoamine Oxidase Inhibitors (MAOIs): The co-administration of Valbenazine with MAOIs (e.g., phenelzine, selegiline) is not recommended. This combination can alter monoamine concentrations in the synapse, potentially attenuating Valbenazine's therapeutic effect or increasing the risk of adverse events like serotonin syndrome. A washout period of at least 14 days is recommended between the use of an MAOI and Valbenazine.[1]
• QT-Prolonging Drugs: Due to Valbenazine's potential to prolong the QT interval, caution should be exercised when it is used concurrently with other medications known to have the same effect, as this could lead to an additive risk of cardiac arrhythmia.[35]

Other Specific Drug Interactions

• Digoxin: Valbenazine is a weak inhibitor of the P-glycoprotein (P-gp) transporter and may increase the concentration of P-gp substrates like digoxin. Patients on this combination may require closer monitoring of digoxin levels.[2]

Disease State Considerations

• Hepatic Dysfunction: As noted, moderate to severe liver impairment necessitates a dose reduction to 40 mg daily due to slower drug clearance.[1]
• Cardiac Conditions: Patients with pre-existing conditions that predispose them to arrhythmia, such as congenital long QT syndrome, should generally avoid Valbenazine.[1]
• Parkinson's Disease: The dopamine-depleting effects of Valbenazine can worsen the motor symptoms of Parkinson's disease, requiring cautious use and monitoring in this population.[38]

Table 4: Guidelines for Valbenazine Dose Adjustment with Concomitant Medications

Interacting Drug Class	Example Drugs	Effect on Valbenazine/Metabolite Exposure	Recommended Valbenazine Dosage
Strong CYP3A4 Inducers	Rifampin, Carbamazepine, Phenytoin, St. John's Wort	Decreases Valbenazine exposure	Concomitant use not recommended
Strong CYP3A4 Inhibitors	Ketoconazole, Ritonavir, Clarithromycin	Increases Valbenazine exposure	Reduce to 40 mg once daily
Strong CYP2D6 Inhibitors	Paroxetine, Fluoxetine, Bupropion	Increases active metabolite ([+]-α-HTBZ) exposure	Reduce to 40 mg once daily
MAOIs	Phenelzine, Selegiline	Potential for attenuated effect or adverse events	Concomitant use not recommended

Regulatory and Developmental History

Development and Manufacturer

Valbenazine was discovered and developed by Neurocrine Biosciences, Inc., a biopharmaceutical company based in San Diego, California.[4]

FDA Approval Timeline

Valbenazine's path to market was marked by several key milestones, reflecting its importance in addressing significant unmet medical needs.

• August 29, 2016: Neurocrine Biosciences submitted a New Drug Application (NDA) to the FDA for Valbenazine for the treatment of tardive dyskinesia.[7]
• October 11, 2016: The FDA accepted the NDA and granted it Priority Review status, a designation reserved for drugs that may offer significant improvements in the treatment of serious conditions.[7]
• April 11, 2017: Valbenazine, under the brand name Ingrezza®, received its initial FDA approval, becoming the first and only medication specifically approved for the treatment of adults with tardive dyskinesia.[3]
• October 5, 2017: The FDA approved the 80 mg capsule strength, simplifying the recommended maintenance dosing to a single capsule, once daily.[27]
• August 18, 2023: The FDA approved a second major indication for Ingrezza®: the treatment of chorea associated with Huntington's disease.[3]
• April 30, 2024: The Ingrezza® Sprinkle formulation was approved by the FDA, providing an important new administration option for patients with dysphagia.[7]

Other Regulatory Designations

In recognition of the need for new treatments for Huntington's disease, Valbenazine was granted Orphan Drug Designation by the FDA on May 10, 2022.[40] This status provides incentives to encourage the development of drugs for rare diseases.

The approval of Valbenazine in 2017 was a watershed moment in psychopharmacology. Before its availability, tardive dyskinesia was largely considered an untreatable and often irreversible side effect of essential antipsychotic medication, with limited and often ineffective management strategies.[16] The arrival of the first FDA-approved therapy fundamentally changed this paradigm. It provided clinicians with a specific, evidence-based tool to directly address TD, which in turn catalyzed a broader increase in awareness, diagnosis, and proactive management of the condition. The approval helped to "change the narrative" surrounding TD, legitimizing it as a treatable disorder and empowering both patients and physicians to address its debilitating symptoms.[22]

Conclusion

Valbenazine (Ingrezza®) represents a significant therapeutic advancement in the management of hyperkinetic movement disorders. Through a process of rational drug design, it was engineered as a highly selective VMAT2 inhibitor that improves upon the profile of older agents by delivering a single, targeted active metabolite, thereby minimizing off-target effects. Its efficacy for treating both tardive dyskinesia and chorea associated with Huntington's disease has been robustly demonstrated in pivotal Phase 3 clinical trials. The drug's favorable pharmacokinetic profile, particularly its long half-life, allows for convenient once-daily dosing. While its safety profile requires careful management—most notably the boxed warning for depression and suicidality in patients with Huntington's disease and the potential for somnolence and QT prolongation—its risks are generally well-characterized and manageable with appropriate patient selection and monitoring. The extensive drug interaction profile, rooted in its CYP450 metabolism, necessitates careful medication review prior to initiation. Ultimately, the approval and clinical integration of Valbenazine have transformed the treatment landscape for tardive dyskinesia, shifting it from a neglected iatrogenic condition to a treatable disorder, and has provided a valuable new option for patients suffering from the debilitating chorea of Huntington's disease.

Works cited

1. Valbenazine (oral route) - Side effects & dosage - Mayo Clinic, accessed September 1, 2025, https://www.mayoclinic.org/drugs-supplements/valbenazine-oral-route/description/drg-20406250
2. Valbenazine for the Treatment of Adults with Tardive Dyskinesia - PMC - PubMed Central, accessed September 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8801818/
3. Valbenazine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 1, 2025, https://go.drugbank.com/drugs/DB11915
4. Valbenazine - Wikipedia, accessed September 1, 2025, https://en.wikipedia.org/wiki/Valbenazine
5. Valbenazine free base | NBI-98854 | CAS#1025504-45-3 - MedKoo Biosciences, accessed September 1, 2025, https://www.medkoo.com/products/7861
6. Valbenazine | C24H38N2O4 | CID 24795069 - PubChem, accessed September 1, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Valbenazine
7. Ingrezza (valbenazine) FDA Approval History - Drugs.com, accessed September 1, 2025, https://www.drugs.com/history/ingrezza.html
8. Compound: VALBENAZINE (CHEMBL2364639) - ChEMBL - EMBL-EBI, accessed September 1, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL2364639
9. Ligand page - valbenazine - IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 1, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8694
10. Valbenazine (NBI-98854, CAS Number: 1025504-45-3) | Cayman Chemical, accessed September 1, 2025, https://www.caymanchem.com/product/26809/valbenazine
11. Valbenazine tosylate | DrugBank Online, accessed September 1, 2025, https://go.drugbank.com/salts/DBSALT002588
12. What is the mechanism of Valbenazine Tosylate? - Patsnap Synapse, accessed September 1, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-valbenazine-tosylate
13. Valbenazine | 1025504-45-3 - ChemicalBook, accessed September 1, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB73118572.htm
14. Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors - LiverTox - NCBI Bookshelf, accessed September 1, 2025, https://www.ncbi.nlm.nih.gov/books/NBK548187/
15. Ingrezza: Uses, Dosage, Side Effects, Warnings - Drugs.com, accessed September 1, 2025, https://www.drugs.com/ingrezza.html
16. KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia | American Journal of Psychiatry, accessed September 1, 2025, https://psychiatryonline.org/doi/10.1176/appi.ajp.2017.16091037
17. Pharmacokinetics, safety and tolerability of valbenazine in Korean, accessed September 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10014685/
18. go.drugbank.com, accessed September 1, 2025, https://go.drugbank.com/drugs/DB11915#:~:text=The%20absolute%20oral%20bioavailability%20of,hours%20after%20administration%20of%20valbenazine.&text=Ingestion%20of%20a%20high%2Dfat,and%20AUC%20by%20approximately%2013%25.
19. INGREZZA® (valbenazine) capsules, for oral use - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/209241s020lbl.pdf
20. Valbenazine Improves Tardive Dyskinesia in Older Adults Over Long Term | Psychiatric News - Psychiatry Online, accessed September 1, 2025, https://www.psychiatryonline.org/doi/10.1176/appi.pn.2025.06.6.30
21. Valbenazine: uses, dosing, warnings, adverse events, interactions - MedCentral, accessed September 1, 2025, https://www.medcentral.com/drugs/monograph/173527-317031/valbenazine-oral
22. The Valbenazine Story: Small Company Makes Big Breakthrough | Psychiatric News, accessed September 1, 2025, https://psychiatryonline.org/doi/10.1176/appi.pn.2017.8b17
23. KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo ..., accessed September 1, 2025, https://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.2017.16091037
24. Valbenazine Phase 3 Study Confirms Safety, Efficacy for Tardive Dyskinesia - MedCentral, accessed September 1, 2025, https://www.medcentral.com/neurology/tardive-dyskinesia/valbenazine-phase-3-study-confirms-safety-efficacy-for-tardive-dyskinesia
25. Characterizing Treatment Effects of Valbenazine for Tardive ..., accessed September 1, 2025, https://www.psychiatrist.com/jcp/valbenazine-for-tardive-dyskinesia-results-from-the-kinect-study/
26. Neurocrine Biosciences Announces Publication of Full KINECT™-HD Phase 3 Study Results of Valbenazine for the Treatment of Chorea Associated with Huntington's Disease in The Lancet Neurology, accessed September 1, 2025, https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-announces-publication-full-kinecttm-hd
27. Neurocrine Announces FDA Approval of 80 mg INGREZZA® (valbenazine) Capsules for the Treatment of Adults with Tardive Dyskinesia (TD) - PR Newswire, accessed September 1, 2025, https://www.prnewswire.com/news-releases/neurocrine-announces-fda-approval-of-80-mg-ingrezza-valbenazine-capsules-for-the-treatment-of-adults-with-tardive-dyskinesia-td-300531471.html
28. FDA Approves Neurocrine Biosciences' Valbenazine for Huntington Disease Chorea, accessed September 1, 2025, https://www.neurologylive.com/view/fda-approves-neurocrine-biosciences-valbenazine-huntington-disease-chorea
29. Neurocrine Biosciences Announces FDA Approval of INGREZZA® (valbenazine) Capsules for the Treatment of Chorea Associated With Huntington's Disease, accessed September 1, 2025, https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-announces-fda-approval-ingrezzar
30. Valbenazine Terminated Phase 3 Trials for Schizophrenia Treatment | DrugBank Online, accessed September 1, 2025, https://go.drugbank.com/drugs/DB11915/clinical_trials?conditions=DBCOND0018504&phase=3&purpose=treatment&status=terminated
31. TD Prescribing Info | INGREZZA® (valbenazine) capsules, accessed September 1, 2025, https://www.ingrezza.com/tardive-dyskinesia/view-pi
32. This label may not be the latest approved by FDA. For current ..., accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/209241s026lbl.pdf
33. Valbenazine: MedlinePlus Drug Information, accessed September 1, 2025, https://medlineplus.gov/druginfo/meds/a617023.html
34. How INGREZZA® (valbenazine) capsules is thought to work - YouTube, accessed September 1, 2025, https://www.youtube.com/watch?v=LkthLnZicwQ
35. Neurocrine Biosciences Announces U.S. FDA Approval of INGREZZA® SPRINKLE (valbenazine) Capsules, accessed September 1, 2025, https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-announces-us-fda-approval-ingrezzar
36. Ingrezza, Ingrezza Sprinkle (valbenazine) dosing, indications, interactions, adverse effects, and more - Medscape Reference, accessed September 1, 2025, https://reference.medscape.com/drug/ingrezza-valbenazine-1000122
37. Ingrezza interactions: Alcohol, medications, and other factors - MedicalNewsToday, accessed September 1, 2025, https://www.medicalnewstoday.com/articles/drugs-ingrezza-interactions
38. Valbenazine Interactions Checker - Drugs.com, accessed September 1, 2025, https://www.drugs.com/drug-interactions/valbenazine.html
39. FDA Approves First Medication to Treat Tardive Dyskinesia | Psychopharmacology, accessed September 1, 2025, https://psychiatryonline.org/doi/10.1176/appi.pn.2017.pp4b1
40. Search Orphan Drug Designations and Approvals - FDA, accessed September 1, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=875022