Valbenazine for tardive dyskinesia

Pharmacokinetics

Valbenazine demonstrates dose-proportional pharmacokinetics after single oral dosages from 40 to 300 mg with no impact of food or fasting status on levels of the active metabolite. Valbenazine has a Tmax of 0.5 to 1.0 hours, with 49% oral bioavailability. The plasma half-life for valbenazine and for NBI-98782 ranges from 15 to 22 hours. The Tmax for NBI-98782 when formed from valbenazine occurs between 4 and 8 hours, with a Cmax of approximately 30 ng/mL. It should be noted that when NBI-98782 is generated from oral tetrabenazine, the mean half-life and Tmax are considerably shorter (6 hours and 1.5 hours, respectively), while the Cmax is much higher (approximately 77 ng/mL) (Table 4).

Valbenazine is metabolized through endogenous esterases to NBI-98782 and NBI-136110. NBI-98782, the active metabolite, is further metabolized through multiple CYP pathways, predominantly 3A4 and 2D6. Neither valbenazine nor its metabolites are inhibitors or inducers of major CYP enzymes. Aside from VMAT2, the results of in vitro studies suggest that valbenazine and its active metabolite are unlikely to inhibit most major drug transporters at clinically relevant concentrations. However, valbenazine increased digoxin levels because of inhibition of intestinal P-glycoprotein; therefore plasma digoxin level monitoring is recommended when these 2 are co-administered.

Efficacy

Efficacy was established in a 6-week, fixed-dosage, double-blind, placebo-controlled trial of adult patients with TD. Eligible participants had:

• DSM-IV diagnosis of antipsychotic-induced TD for ≥3 months before screening and moderate or severe TD, as indicated by AIMS item 8 (severity of abnormal movement), which was rated by a blinded, external reviewer using a video of the participant’s AIMS assessment at screening
• a DSM-IV diagnosis of schizophrenia or schizoaffective disorder or mood disorder (and stable per investigator)
• Brief Psychiatric Rating Scale score <50 at screening.

Exclusion criteria included clinically significant and unstable medical conditions within 1 month before screening; comorbid movement disorder (eg, parkinsonism, akathisia, truncal dystonia) that was more prominent than TD; and significant risk for active suicidal ideation, suicidal behavior, or violent behavior.² Participants had a mean age of 56, 52% were male, and 65.7% of participants in the valbenazine 40-mg group had a schizophrenia spectrum disorder diagnosis, as did 65.8% in both the placebo and valbenazine 80-mg arms.

Antipsychotic treatments were permitted during the trial and >85% of participants continued taking these medications during the study. Participants (N = 234) were randomly allocated in a 1:1:1 manner to valbenazine 40 mg, 80 mg, or matched placebo. The primary outcome was change in AIMS total score (items 1 to 7) assessed by central, independent raters. Baseline AIMS scores were 9.9 ± 4.3 in the placebo group, and 9.8 ± 4.1 and 10.4 ± 3.6 in the valbenazine 40-mg and 80-mg arms, respectively.²

Outcome. A fixed-sequence testing procedure to control for family-wise error rate and multiplicity was employed, and the primary endpoint was change from baseline to Week 6 in AIMS total score (items 1 to 7) for valbenazine 80 mg vs placebo. Valbenazine, 40 mg, was associated with a 1.9 point decrease in AIMS score, while valbenazine, 80 mg, was associated with a 3.2 point decrease in AIMS score, compared with 0.1 point decrease for placebo (P < .05 for valbenazine, 40 mg, P < .001 for valbenazine, 80 mg). This difference for the 40-mg dosage did not meet the prespecified analysis endpoints; however, for the 80-mg valbenazine dosage, the effect size for this difference (Cohen’s d) was large 0.90. There also were statistically significant differences between 40 mg and 80 mg at weeks 2, 4, and 6 in the intent-to-treat population. Of the 79 participants, 43 taking the 80-mg dosage completed a 48-week extension. Efficacy was sustained in this group; however, when valbenazine was discontinued at Week 48, AIMS scores returned to baseline after 4 weeks.

Tolerability

Of the 234 randomized patients, 205 (87.6%) completed the 6-week trial. Discontinuations due to adverse events were low across all treatment groups: 2.6% and 2.8% in the placebo and valbenazine 40-mg arms, respectively, and 3.8% in valbenazine 80-mg cohort. There was no safety signal based on changes in depression, suicidality, parkinsonism rating, or changes in schizophrenia symptoms. Because valbenazine can cause somnolence, patients should not perform activities requiring mental alertness (eg, operating a vehicle or hazardous machinery) until they know how they will be affected by valbenazine.

Valbenazine should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, assess the QT interval before increasing the dosage.