What is the half-life of Trintellix (vortioxetine)?

Half-Life of Trintellix (Vortioxetine)

Trintellix (vortioxetine) has a mean terminal half-life of approximately 66 hours, which allows for once-daily dosing and typically requires about two weeks to reach steady-state plasma concentrations. 1

Pharmacokinetic Profile

The pharmacokinetics of vortioxetine are characterized by:

• Linear and dose-proportional pharmacokinetics across the therapeutic dose range (5-20 mg)
• Mean terminal half-life of approximately 66 hours
• Steady-state plasma concentrations generally achieved within two weeks of dosing
• Absolute oral bioavailability of 75%
• Time to maximum plasma concentration (Tmax) of 7-11 hours after dosing
• No effect of food on pharmacokinetics

Metabolism and Excretion

Vortioxetine is extensively metabolized primarily through oxidation via several cytochrome P450 isozymes:

• CYP2D6 (primary enzyme)
• CYP3A4/5
• CYP2C19
• CYP2C9
• CYP2A6
• CYP2C8
• CYP2B6

Following metabolism, vortioxetine undergoes subsequent glucuronic acid conjugation. The major metabolite is pharmacologically inactive, and negligible amounts of unchanged vortioxetine are excreted in the urine 1, 2.

Clinical Implications of Long Half-Life

The long half-life of vortioxetine (66 hours) has several important clinical implications:

1. Steady-State Achievement: Requires approximately 2 weeks to reach steady-state plasma concentrations
2. Missed Doses: Occasional missed doses are less likely to cause significant fluctuations in blood levels compared to antidepressants with shorter half-lives 3
3. Discontinuation: Lower risk of discontinuation or withdrawal syndromes due to gradual washout 3
4. Drug Interactions: Potential for prolonged drug interactions, particularly with MAOIs

Special Populations

The long half-life of vortioxetine may be further prolonged in certain populations:

• Obesity: Studies have shown that the washout half-life is significantly prolonged in obese individuals (3.26 days) compared to normal-weight controls (2.21 days) 4
• CYP2D6 Poor Metabolizers: Poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers 1

Comparison to Other Antidepressants

Vortioxetine's half-life of 66 hours is considerably longer than many other commonly prescribed antidepressants:

• Fluoxetine is another antidepressant with a long half-life
• Most SSRIs and SNRIs have shorter half-lives (typically 24 hours or less)
• The long half-life contributes to vortioxetine's once-daily dosing regimen 2, 3

Clinical Monitoring Considerations

Due to the long half-life:

• Allow at least 14 days between discontinuation of vortioxetine and initiation of an MAOI
• In obese patients, this washout period may need to be extended further to avoid potential serotonin syndrome 4
• When switching from vortioxetine to other antidepressants, a gradual cross-titration approach may be appropriate due to the extended elimination time

The long half-life of vortioxetine contributes to its overall favorable pharmacokinetic profile, allowing for once-daily dosing and potentially reducing the impact of occasional missed doses on therapeutic efficacy.