"The U.S. Food and Drug Administration today approved Brintellix (vortioxetine) to treat adults with major depressive disorder.
Major depressive disorder (MDD), commonly referred to as depression, is a mental disorder characterized by mo"...
Mechanism Of Action
The mechanism of the antidepressant effect of vortioxetine is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through inhibition of the reuptake of serotonin (5-HT). It also has several other activities including 5-HT3 receptor antagonism and 5-HT1A receptor agonism. The contribution of these activities to vortioxetine's antidepressant effect has not been established.
Vortioxetine binds with high affinity to the human serotonin transporter (Ki=1.6 nM), but not to the norepinephrine (Ki=113 nM) or dopamine (Ki > 1000 nM) transporters. Vortioxetine potently and selectively inhibits reuptake of serotonin (IC50=5.4 nM). Vortioxetine binds to 5-HT3 (Ki=3.7 nM), 5-HT1A (Ki=15 nM), 5-HT7 (Ki=19 nM), 5-HT1D (Ki=54 nM), and 5-HT1B (Ki=33 nM), receptors and is a 5-HT3, 5-HT1D, and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, and 5-HT1A receptor agonist.
In humans, the mean 5-HT transporter occupancy, based on the results from 2 clinical PET studies using 5-HTT ligands ([11C]-MADAM or [11C]-DASB), was approximately 50% at 5 mg/day, 65% at 10 mg/day and approximately 80% at 20 mg/day in the regions of interest.
Effect on Cardiac Repolarization
The effect of vortioxetine 10 mg and 40 mg administered once daily on QTc interval was evaluated in a randomized, double-blind, placebo-, and active-controlled (moxifloxacin 400 mg), four-treatment-arm parallel study in 340 male subjects. In the study the upper bound of the one-sided 95% confidence interval for the QTc was below 10 ms, the threshold for regulatory concern. The oral dose of 40 mg is sufficient to assess the effect of metabolic inhibition.
Effect on Driving Performance
In a clinical study in healthy subjects, BRINTELLIX did not impair driving performance, or have adverse psychomotor or cognitive effects following single and multiple doses of 10 mg/day. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that BRINTELLIX therapy does not affect their ability to engage in such activities.
Vortioxetine pharmacological activity is due to the parent drug. The pharmacokinetics of vortioxetine (2.5 mg to 60 mg) are linear and dose-proportional when vortioxetine is administered once daily. The mean terminal half-life is approximately 66 hours, and steady-state plasma concentrations are typically achieved within two weeks of dosing.
The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose (Tmax). Steady-state mean Cmax values were 9, 18, and 33 ng/mL following doses of 5, 10, and 20 mg/day. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed.
The apparent volume of distribution of vortioxetine is approximately 2600 L, indicating extensive extravascular distribution. The plasma protein binding of vortioxetine in humans is 98%, independent of plasma concentrations. No apparent difference in the plasma protein binding between healthy subjects and subjects with hepatic (mild, moderate) or renal (mild, moderate, severe, ESRD) impairment is observed.
Metabolism and Elimination
Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers.
Following a single oral dose of [14C]-labeled vortioxetine, approximately 59% and 26% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours. The presence of hepatic (mild or moderate) or renal impairment (mild, moderate, severe and ESRD) did not affect the apparent clearance of vortioxetine.
The efficacy of BRINTELLIX in treatment for MDD was established in six 6 to 8 week randomized, double-blind, placebo-controlled, fixed-dose studies (including one study in the elderly) and one maintenance study in adult inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD.
Adults (aged 18 years to 75 years)
The efficacy of BRINTELLIX in patients aged 18 years to 75 years was demonstrated in five 6 to 8 week, placebo-controlled studies (Studies 1 to 5 in Table 4). In these studies, patients were randomized to BRINTELLIX 5 mg, 10 mg, 15 mg or 20 mg or placebo once daily. For patients who were randomized to BRINTELLIX 15 mg/day or 20 mg/day, the final doses were titrated up from 10 mg/day after the first week.
The primary efficacy measures were the Hamilton Depression Scale (HAMD-24) total score in Study 2 and the Montgomery-Asberg Depression Rating Scale (MADRS) total score in all other studies. In each of these studies, at least one dose group of BRINTELLIX was superior to placebo in improvement of depressive symptoms as measured by mean change from baseline to endpoint visit on the primary efficacy measurement (see Table 4). Subgroup analysis by age, gender or race did not suggest any clear evidence of differential responsiveness. Two studies of the 5 mg dose in the U.S. (not represented in Table 4) failed to show effectiveness.
Elderly Study (aged 64 years to 88 years)
The efficacy of BRINTELLIX for the treatment of MDD was also demonstrated in a randomized, double-blind, placebo-controlled, fixed-dose study of BRINTELLIX in elderly patients (aged 64 years to 88 years) with MDD (Study 6 in Table 4). Patients meeting the diagnostic criteria for recurrent MDD with at least one previous major depressive episode before the age of 60 years and without comorbid cognitive impairment (Mini Mental State Examination score < 24) received BRINTELLIX 5 mg or placebo.
Table 4: Primary Efficacy Results of 6 Week to 8 Week
|Study No. [Primary Measure]||Treatment Group||Number of Patients||Mean Baseline Score (SD)||LS Mean Change from Baseline (SE)||Placebo-subtracted Difference1 (95% CI)|
|Study 1 [MADRS] Non-US Study||BRINTELLIX (5 mg/day)‡||108||34.1 (2.6)||-20.4 (1.0)||-5.9 (-8.6, -3.2)|
|BRINTELLIX (10 mg/day)‡||100||34.0 (2.8)||-20.2 (1.0)||-5.7 (-8.5, -2.9)|
|Placebo||105||33.9 (2.7)||-14.5 (1.0)||-|
|Study 2 [HAMD-24] Non-US Study||BRINTELLIX (5 mg/day)||139||32.2 (5.0)||-15.4 (0.7)||-4.1 (-6.2, -2.1)|
|BRINTELLIX (10 mg/day)‡||139||33.1 (4.8)||-16.2 (0.8)||-4.9 (-7.0, -2.9)|
|Placebo||139||32.7 (4.4)||-11.3 (0.7)||--|
|Study 3 [MADRS] Non-US Study||BRINTELLIX (15 mg/day) ‡||149||31.8 (3.4)||-17.2 (0.8)||-5.5 (-7.7, -3.4)|
|BRINTELLIX (20 mg/day) ‡||151||31.2 (3.4)||-18.8 (0.8)||-7.1 (-9.2, -5.0)|
|Placebo||158||31.5 (3.6)||-11.7 (0.8)||--|
|Study 4 [MADRS] US Study||BRINTELLIX (15 mg/day)||145||31.9 (4.1)||-14.3 (0.9)||-1.5 (-3.9, 0.9)|
|BRINTELLIX (20 mg/day) ‡||147||32.0 (4.4)||-15.6 (0.9)||-2.8 (-5.1, -0.4)|
|Placebo||153||31.5 (4.2)||-12.8 (0.8)||--|
|Study 5 [MADRS] US Study||BRINTELLIX (10 mg/day)||154||32.2 (4.5)||-13.0 (0.8)||-2.2 (-4.5, 0.1)|
|BRINTELLIX (20 mg/day) ‡||148||32.5 (4.3)||-14.4 (0.9)||-3.6 (-5.9, -1.4)|
|Placebo||155||32.0 (4.0)||-10.8 (0.8)||--|
|Study 6 (elderly) [HAMD-24] US and Non-US||BRINTELLIX (5 mg/day) ‡||155||29.2 (5.0)||-13.7 (0.7)||-3.3 (-5.3, -1.3)|
|Placebo||145||29.4 (5.1)||-10.3 (0.8)||-|
|SD: standard deviation; SE: standard error; LS Mean:
least-squares mean; CI: unadjusted confidence interval.
†Difference (drug minus placebo) in least-squares mean change from baseline.
†Doses that are statistically significantly superior to placebo after adjusting for multiplicity.
Time Course of Treatment Response
In the 6 to 8 week placebo-controlled studies, an effect of BRINTELLIX based on the primary efficacy measure was generally observed starting at Week 2 and increased in subsequent weeks with the full antidepressant effect of BRINTELLIX generally not seen until Study Week 4 or later. Figure 4 depicts time course of response in U.S. based on the primary efficacy measure (MADRS) in Study 5.
Figure 4: Change from
Baseline in MADRS Total Score by Study Visit (Week) in Study 5
Figure 5: Difference from
Placebo in Mean Change from Baseline in MADRS Total Score at Week 6 or Week 8
†Results (point estimate and unadjusted 95% confidence interval) are from mixed model for repeated measures (MMRM) analysis. In Studies 1 and 6, the primary analysis was not based on MMRM and in Studies 2 and 6 the primary efficacy measure was not based on MADRS.
In a non-US maintenance study (Study 7 in Figure 6), 639 patients meeting DSM-IV-TR criteria for MDD received flexible doses of BRINTELLIX (5 mg or 10 mg) once daily during an initial 12 week open-label treatment phase; the dose of BRINTELLIX was fixed during Weeks 8 to 12. Three hundred ninety six (396) patients who were in remission (MADRS total score ≤ 10 at both Weeks 10 and 12) after open-label treatment were randomly assigned to continuation of a fixed dose of BRINTELLIX at the final dose they responded to (about 75% of patients were on 10 mg/day) during the open-label phase or to placebo for 24 to 64 weeks. Approximately 61% of randomized patients satisfied remission criterion (MADRS total score ≤ 10) for at least 4 weeks (since Week 8), and 15% for at least 8 weeks (since Week 4). Patients on BRINTELLIX experienced a statistically significantly longer time to have recurrence of depressive episodes than did patients on placebo. Recurrence of depressive episode was defined as a MADRS total score ≥ 22 or lack of efficacy as judged by the investigator.
Figure 6: Kaplan-Meier Estimates of Proportion of
Patients with Recurrence (Study 7)
Last reviewed on RxList: 9/17/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Brintellix Information
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