Chemical formula: C₁₈H₂₂N₂S Molecular mass: 298.45 g/mol PubChem compound: 71768094
The mechanism of action of vortioxetine is thought to be related to its direct modulation of serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter.
Nonclinical data indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter, leading to modulation of neurotransmission in several systems, including predominantly the serotonin but probably also the norepinephrine, dopamine, histamine, acetylcholine, GABA and glutamate systems. This multimodal activity is considered responsible for the antidepressant and anxiolytic-like effects and the improvement of cognitive function, learning and memory observed with vortioxetine in animal studies. However, the precise contribution of the individual targets to the observed pharmacodynamic profile remains unclear and caution should be applied when extrapolating animal data directly to man.
In humans, two positron emission tomography (PET) studies have been conducted using 5-HT transporter ligands (11C-MADAM or 11C-DASB) to quantify the 5-HT transporter occupancy in the brain across different dose levels. The mean 5-HT transporter occupancy in the raphe nuclei was approximately 50% at 5 mg/day, 65% at 10 mg/day and increased to above 80% at 20 mg/day.
Vortioxetine is slowly, but well absorbed after oral administration and the peak plasma concentration is reached within 7 to 11 hours. Following multiple dosing of 5, 10, or 20 mg/day, mean Cmax values of 9 to 33 ng/mL were observed. The absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed.
The mean volume of distribution (Vss) is 2,600 L, indicating extensive extravascular distribution. Vortioxetine is highly bound to plasma proteins (98 to 99%) and the binding appears to be independent of vortioxetine plasma concentrations.
Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by CYP2D6 and to a minor extent CYP3A4/5 and CYP2C9, and subsequent glucuronic acid conjugation.
No inhibitory or inducing effect of vortioxetine was observed in the drug-drug interaction studies for the CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5. Vortioxetine is a poor P-gp substrate and inhibitor.
The major metabolite of vortioxetine is pharmacologically inactive.
The mean elimination half-life and oral clearance are 66 hours and 33 L/h, respectively. Approximately ⅔ of the inactive vortioxetine metabolites are excreted in the urine and approximately ⅓ in the faeces. Only negligible amounts of vortioxetine are excreted in the faeces. Steady-state plasma concentrations are achieved in approximately 2 weeks.
The pharmacokinetics are linear and time independent in the dose range studied (2.5 to 60 mg/day).
In accordance with the half-life, the accumulation index is 5 to 6 based on AUC0-24h following multiple doses of 5 to 20 mg/day.
In elderly healthy subjects (aged ≥65 years; n=20), the exposure to vortioxetine increased up to 27% (Cmax and AUC) compared to young healthy control subjects (aged ≤45 years) after multiple doses of 10 mg/day. The lowest effective dose of 5 mg vortioxetine once daily should always be used as the starting dose in patients ≥65 years. However, caution should be exercised when prescribing to elderly patients at doses higher than 10 mg vortioxetine once daily.
Following a single dose of 10 mg vortioxetine, renal impairment estimated using the Cockcroft-Gault formula (mild, moderate, or severe; n=8 per group) caused modest exposure increases (up to 30%), compared to healthy matched controls. In patients with end-stage renal disease, only a small fraction of vortioxetine was lost during dialysis (AUC and Cmax were 13% and 27% lower, respectively; n=8) following a single 10 mg dose of vortioxetine. No dose adjustment is needed.
Following a single dose of 10 mg vortioxetine, no impact of mild or moderate hepatic impairment (Child-Pugh Criteria A or B; n=8 per group) was observed on the pharmacokinetics of vortioxetine (changes in AUC were less than 10%). No dose adjustment is needed. Vortioxetine has not been studied in patients with severe hepatic impairment and caution should be exercised when treating these patients.
The plasma concentration of vortioxetine was approximately two times higher in CYP2D6 poor metabolisers than in extensive metabolisers. Co-administration of strong CYP3A4/2C9 inhibitors to CYP2D6 poor metabolisers could potentially result in higher exposure.
In CYP2D6 ultra-rapid metabolisers, the plasma concentration of vortioxetine 10 mg/day were between those obtained in extensive metabolisers at 5 mg/day and 10 mg/day. Depending on individual patient response, a dose adjustment may be considered.
Administration of vortioxetine in the general toxicity studies in mice, rats and dogs was mainly associated with CNS-related clinical signs. These included salivation (rat and dog), pupil dilatation (dog), and two incidences of convulsions in dogs in the general toxicity study programme. A no-effect level for convulsions was established with a corresponding safety margin of 5 considering the maximum recommended therapeutic dose of 20 mg/day. Target organ toxicity was restricted to kidneys (rats) and liver (mice and rats). The changes in the kidney in rats (glomerulonephritis, renal tubular obstruction, crystalline material in renal tubule) and in the liver of mice and rats (hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, crystalline material in bile ducts) were seen at exposures more than 10-fold (mice) and 2-fold (rats) the human exposure at the maximum recommended therapeutic dose of 20 mg/day. These findings were mainly attributed to rodent-specific vortioxetine-related crystalline material obstruction of the renal tubules and the bile ducts, respectively, and considered of low risk to humans.
Vortioxetine was not genotoxic in a standard battery of in vitro and in vivo tests.
Based on results from conventional 2-year carcinogenicity studies in mice or rats, vortioxetine is not considered to pose a risk of carcinogenicity in humans.
Vortioxetine had no effect on rat fertility, mating performance, reproductive organs, or sperm morphology and motility. Vortioxetine was not teratogenic in rats or rabbits, but reproductive toxicity in terms of effects on foetal weight and delayed ossification were seen in the rat at exposures more than 10-fold the human exposure at the maximum recommended therapeutic dose of 20 mg/day. Similar effects were seen in the rabbit at sub-therapeutic exposure.
In a pre- and post-natal study in rats, vortioxetine was associated with increased pup mortality, reduced bodyweight gain, and delayed pup development at doses that did not result in maternal toxicity and with associated exposures similar to those achieved in humans following administration of vortioxetine 20 mg/day.
Vortioxetine-related material was distributed to the milk of lactating rats.
In juvenile toxicity studies in rats, all vortioxetine treatment-related findings were consistent with those noted in adult animals.
Environmental risk assessment studies have shown that vortioxetine has the potential to be persistent, bioaccumulative and toxic to the environment (risk to fish). However, by recommended patient usage vortioxetine is considered to pose negligible risk to the aquatic and terrestrial environment.
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