Vortioxetine Hydrobromide
Vortioxetine hydrobromide was approved by the U.S. Food and Drug Administration (FDA) on September 30, 2013, then approved by European Medicine Agency (EMA) on Dec 18, 2013. It was co-developed by Takeda & Lundbeck Corporation, and marketed as Brintellix® by Takeda in the US and by Lundbeck Corporation in EU. However, Brintellix® renamed Trintellix® in U.S. to avoid name confusion by Takeda and Lundbeck in June of 2016.
The mechanism of the antidepressant effect of Vortioxetine is not fully understood. It is an inhibitor of serotonin (5-HT) reuptake and that is thought to be a mechanism of its action. It is also an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors and an antagonist at 5-HT3, 5-HT1D and 5-HT7 receptors. The contribution of each of these activities to Vortioxetine's antidepressant effect has not been established. It is considered to be the first and only compound with this combination of pharmacodynamic activity. It is indicated for the treatment of major depressive disorder (MDD).
Brintellix® is available as film-coated tablet for oral use, containing 5, 10, 15 or 20 mg of free Vortioxetine. The recommended dose is 10 mg administered orally once daily without regard to meals.
Update Date：2016-05-16
- Drug Name：
- Vortioxetine Hydrobromide
- Research Code：
- LuAA-21004
- Trade Name：
- Brintellix®
- MOA：
- Serotonin modulator and stimulator
- Indication：
- Major depressive disorder (MDD)
- Status：
- Approved
- Company：
- Takeda (Originator) , Lundbeck
- Sales：
-
$281 Million (Y2015);
$123.5 Million (Y2014); - ATC Code：
- N06AX26
Update Date：2016-05-16
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-09-30 | Marketing approval | Trintellix | Major depressive disorder (MDD) | Tablet, Film coated | Eq. 5 mg/10 mg/15 mg/20 mg Vortioxetine | Takeda |
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-12-18 | Marketing approval | Brintellix | Major depressive disorder (MDD) | Tablet, Film coated | 5 mg/10 mg/15 mg | Lundbeck |
Update Date：2015-08-27
|
Molecular Weight | 379.36 | ||||||||||||
| Formula | C18H22N2S•HBr | |||||||||||||
| CAS No. |
508233-74-7 (Vortioxetine); 960203-27-4 (Vortioxetine HBr); |
|||||||||||||
| Chemical Name | 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide | |||||||||||||
| Vortioxetine （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-09-02
Update Date：2015-11-25
1. WO03029232A1 / US7138407B2.
2. WO2014128207A1.
1. WO2007144005A1 / US8722684B2.
2. WO2009062517A1 / US2011201617A1.
3. WO2010094285A1 / US8598348B2.
4. WO2013102573A1 / US2014343287A1.
5. CN104098530A.
1. WO2014161976A1.
2. CN103788019A.
3. CN103788020A.
4. CN103936694A.
5. CN104109135A.
6. CN104230852A.
7. CN104130212A.
1. WO2014191548A1.
Update Date：2016-06-08
Mechanism of Action
Vortioxetine is a selective serotonin reuptake inhibitor with additional activity at five serotonin receptors: 5-HT3 (potent antagonist), 5-HT7 (weak antagonist), 5-HT1D (moderate antagonist), 5-HT1B (moderate to weak partial agonist), and 5-HT1A (moderate agonist).
Vortioxetine showed high affinity to the cloned human serotonin transporter (Ki = 1.6 nM) and inhibited reuptake of serotonin (cIC50 = 5.4 nM).
Vortioxetine showed lower affinity to the cloned human norepinephrine transporters (Ki = 113 nM, cIC50 = 107 nM) and dopamine transporters (Ki and cIC50 >1000 nM).
Vortioxetine increased 5-HT level in brain by inhibiting 5-HT reuptake.
In Vivo Efficacy
Vortioxetine showed an antidepressant or anxiolytic-like profile in behavioural assay:
● Mouse forced swim test: Antidepressant effect at 15.8 mg/kg s.c.
● Novelty-induced suppression of feeding model: Antidepressant effect at MED = 5 mg/kg/day p.o. accompanied by enhanced cell proliferation and maturation in the hippocampus.
● Foot shock-induced ultrasonic vocalization: Anxiolytic-like effect at MED = 3.9 mg/kg s.c.
● Social interaction test: Anxiolytic-like effect at 1 mg/kg, p.o.
Update Date：2016-06-08
Absorption of Vortioxetine HBr
Exhibited a linear pharmacokinetics in humans following oral dosing. The increase in Cmax and AUCinf appeared to be dose-proportional in the dose range of 5 to 20 mg vortioxetine.
Had a low oral bioavailability in rats (6.7%), and moderate in dogs (48%)
Was absorbed slowly (Tmax = 9.1-10 h) in humans and dogs (Tmax = 6 h), but quickly in rats (Tmax = 1 h)
Had a half-life of 60.6-69.4 h in humans, much longer than those in the rats (3.8 h) and dogs (7.3 h), after oral administration.
Had a high clearance in rats (4.93 L/h/kg) and dogs (1.82 L/h/kg), compared to liver blood flow, after intravenous administration. The Cl/F was 40 L/h in humans after oral administration.
Showed an extensive tissue distribution in rats and dogs, with an apparent volume of distribution at 16.2 L/kg and 21.2 L/kg, respectively, after intravenous administration. The apparent volume of distribution in humans was 2773-3288 L after oral administration.
Distribution of Vortioxetine HBr
Exhibited high plasma protein binding in humans (>98.8%), rats (>98.8%), mice (>98.8%), rabbits (>98.8%) and dogs (>98.8%).
Had a Cb:Cp ratio of 0.34-0.65 in humans, suggesting the drug did not well distribute into red blood cells.
In male Listar Hooded rats following a single oral administration:
● The drug and metabolites were extensively distributed to most tissues, including blood-brain barrier.
● Relatively higher drug concentration tissues were observed in liver, kidneys, lungs, pituitary gland and bone marrow, compared to that in blood.
● The radioactivity concentration was detectable in liver (1.9 μg eq./g), eyes (2.11 μg eq./g) and kidneys (0.652 μg eq./g) after 24 h post-dose, compared to blood (0.701 μg eq./g).
● Had a higher concentrations of drug-related material in melanin containing tissues of pigmented rats (Lister Hooded), compared to albino rats (Han Wistar).
Metabolism of Vortioxetine HBr
M3 (Lu AA39835 glucuronide), M4 (b, Lu AA34443 glucuronide), Lu AA34443, and M12 were considered as the major metabolites in human plasma.
CYP2D6, CYP2C9, CYP3A4/5, CYP2A6, CYP2C8, CYP2C19, and CYP2B6 were the cytochrome P450 isozymes responsible for most of vortioxetine metabolism, but CYP2D6 was the primary metabolic enzyme.
Lu AA34443, a major circulating metabolite, did not bind to the main receptors related to effectiveness in vitro.
Excretion of Vortioxetine HBr
Was predominantly eliminated in urine in humans, with Lu AA34443 (9.4%) as the major component in human urine. There was no detectable unchanged vortioxetine in human urine.
Was predominantly eliminated in feces in mice, rats and dogs, with Lu AA34443 as the major component in mouse, rat and dog feces.
Drug-Drug interaction
Both vortioxetine and the metabolite Lu AA34443 did not inhibit CYP2C8 ([I]/Ki = 0.012), 2C9 ([I]/Ki = 0.004-0.007).
Lu AA34443 did not inhibit CYP2C8 ([I]/Ki = 0.024), and Lu AA39835 did not inhibit CYP2C19 ([I]/Ki >0.004) and 2C9 ([I]/Ki = 0.0004).
In vitro, vortioxetine and the metabolite Lu AA34443 had no induction of CYP1A2, 2C8, 2C9, 2C19 and 3A4/5.
Vortioxetine was a substrate for P-gp, and a moderate inhibitor (IC50 = 4.4 μM).
Update Date：2016-06-08
Single-Dose Toxicity
Single-dose oral and intravenous administration of vortioxetine in mice and rats:
● Mouse MTD: 200 mg/kg (p.o.), and 20 mg/kg (i.v.)
● Rat MTD: 500 mg/kg, and 20 mg/kg (i.v.)
Repeated-Dose Toxicity
Repeat-dose oral administration of vortioxetine in rats (up to 26 weeks) and dogs (up 52 weeks):
● The main findings were clinical signs on the central nervous system in all species and changes of liver and kidneys in rodents.
● For rats: The NOAEL was determined as 10 mg/kg/BID, which was 2 × (male) and 1.6 × (female) MRHD, with kidneys and liver toxicities (including crystalline material found in the bile ducts and renal tract).
● For dogs: The NOAEL was determined as 3.75 (male) and 5 (female) mg/kg/QD in 52-week study, which was 2 × and 3 × MRHD, with pupillary dilation and several organs weight changes.
Safety Pharmacology
Vortioxetine did not impair central nervous system as evident by an Irwin test in rats.
In behavioral studies in dogs, only sedation was noted at clinically relevant plasma exposures.
In cardiovascular studies, vortioxetine was a weak reversible inhibitor of the hERG channel (IC50 = 3.3 μM) and an inhibitor of human cardiac SCN5A Na+ channels (IC50 = 930 nM).
In isolated right atrium from rat, vortioxetine did not affect basal heart rate, but modify isoprenaline's dose response.
In anesthetized rabbits and conscious dog (10 and 6 mg/kg, respectively, i.v.): Increased heart rate and the NOEL for increased heart rate was 6 and 3 mg/kg in rabbits and dogs, respectively.
In anesthetized ventilated guinea pigs, vortioxetine decreased heart rate at ≥10 mg/kg (i.v.).
Vortioxetine had minimal effects on respiration function.
Vortioxetine may affect the gastrointestinal system by decreasing gastric emptying in rats.
Genotoxicity
Vortioxetine was neither mutagenic in the Ames assay, nor clastogenic in the in vitro chromosome aberration assay and in the in vivo rat bone marrow micronucleus assay.
Reproductive and Developmental Toxicity
Fertility and early embryo development:
● The NOAEL for male fertility was 60 mg/kg/BID (58 × MRHD).
● The NOAEL for female fertility and early embryonic development was 60 mg/kg/BID (58 × MRHD).
Embryo-fetal development:
● For rats: The NOAEL for maternal toxicity was ≥40 mg/kg/ BID and for fetal developmental toxicity was 5 mg/kg/BID. There were no drug-related malformations in rats at doses up to 80 mg/kg/BID.
● For rabbits: The NOAEL for maternal toxicity was not determined, less than 1 mg/kg/BID, and for fetal developmental toxicity was1 mg/kg/BID.
Pre- and postnatal development: The NOAEL for maternal toxicity was 5 mg/kg/BID. The NOAEL for pup development was 5 mg/kg/BID and for post-weaning development, sexual development, mating, and fertility was 60 mg/kg/BID.
Vortioxetine and its metabolites distributed throughout maternal and fetal tissue and were present in milk secretion.
Carcinogenicity
For mice: The NOAEL (both neoplastic and non-neoplastic changes) was 15 mg/kg/day in males and 30 mg/kg/day in females, respectively.
For rats: The NOAEL (both neoplastic and non-neoplastic findings) was 2 mg/kg/BID in males and 15 mg/kg/BID in females, respectively. Neoplastic findings related to oral administration of vortioxetine were observed in the liver and mesenteric lymph node.
Incidence of rectum polypoid adenoma increased in female rats but should not be concerned as carcinogenicity risk in human.
