How Ingrezza (Valbenazine) Works
Ingrezza works by reversibly inhibiting vesicular monoamine transporter 2 (VMAT2), a presynaptic protein that regulates the packaging and release of dopamine and other monoamines from neuronal vesicles into the synapse, thereby reducing excessive dopaminergic activity that underlies movement disorders. 1, 2
Mechanism of Action
Primary Pharmacological Target
- Valbenazine selectively inhibits VMAT2 (Ki ~ 150 nM) with no appreciable binding to VMAT1 (Ki > 10 µM), making it highly selective for the neuronal transporter over the peripheral form 1
- The drug is a prodrug that is converted to its active metabolite [+]-α-dihydrotetrabenazine ([+]-α-HTBZ), which binds VMAT2 with even higher affinity (Ki ~ 3 nM) 1, 2
- This reversible inhibition modulates dopamine release during nerve communication by reducing the amount of dopamine packaged into synaptic vesicles available for release 3, 2
Receptor Selectivity Profile
- Neither valbenazine nor its active metabolite bind to dopamine receptors (including D2), serotonergic receptors (including 5HT2B), adrenergic, histaminergic, or muscarinic receptors (Ki > 5000 nM for all) 1
- This selectivity distinguishes it from antipsychotics, which act on postsynaptic dopamine receptors, while VMAT2 inhibitors act presynaptically to reduce dopamine availability 2
Clinical Application
Approved Indications
- FDA-approved for treating tardive dyskinesia in adults, a hyperkinetic movement disorder caused by chronic antipsychotic use that creates a hyperdopaminergic state 4, 3, 5
- Also approved for chorea associated with Huntington's disease, where excessive dopaminergic activity contributes to involuntary movements 4, 1
Therapeutic Rationale
- By reducing presynaptic dopamine release through VMAT2 inhibition, valbenazine counteracts the hyperdopaminergic state that drives the involuntary, repetitive, stereotypic movements characteristic of these disorders 3, 2
- The mechanism addresses the underlying pathophysiology rather than simply blocking postsynaptic receptors 2
Pharmacological Advantages
- Once-daily dosing due to the prodrug design and pharmacokinetic profile 6
- Better tolerability profile compared to tetrabenazine, an older VMAT2 inhibitor, due to selective inhibition and modified chemical structure 6, 2
- Clinically significant effect size (d=0.90 for 80 mg dose) in reducing tardive dyskinesia symptoms 6
Important Clinical Considerations
- May cause QT prolongation, particularly in CYP2D6 poor metabolizers or patients taking strong CYP2D6 or CYP3A4 inhibitors, with predicted QT increases of 9.6-14.7 msec depending on dose and metabolizer status 1
- Dosage reduction required for CYP2D6 poor metabolizers and patients with moderate to severe hepatic impairment due to increased exposure to the active metabolite 1
- No renal dose adjustment needed as the drug does not undergo primary renal clearance 1