Monday, October 22, 2018

Vortioxetine



In the world of pharmacy, mental illnesses are some of the most difficult to understand and treat. Mechanisms that lead to these disorders are complex, and while most drugs are designed to raise or lower the level of certain chemicals, the exact chain of events that leads to treatment of the disease is often unknown. In the case of Major Depressive Disorder (MDD), inhibition of serotonin transporters (SERT) and antagonism of synaptic serotonin receptors (5-HT receptors) have been shown to treat MDD and many drugs on the market today have these qualities. Monoamines, synthesized from halogenated benzenes, have demonstrated some of these qualities and have been investigated by pharmacists as potential MDD drugs. This led to the discovery of Vortioxetine, a molecule capable of both SERT inhibition and 5-HT binding.
The dual activity displayed by Vortioxetine was the target of an iterative assay performed by Lundbeck that scanned all known compounds in their database. Molecules that produced hits on SERT assays were screened for 5-HT binding affinity. Several compounds demonstrated dual activity, but Vortioxetine had an unexpected effect on the 5-HT receptors. Like the others, it was antagonistic to multiple synaptic serotonin receptors. However, Vortioxetine was agonistic of 5-HT1A, a presynaptic receptor that plays a role in the reuptake of serotonin. It was theorized this unintended response reduced the onset of serotonin syndrome, a condition common to antidepressant medication that weakens the effectiveness of the drug. This effect gave it an advantage over previous antidepressants on the market. These findings were demonstrated in vitro and further studied in rat models. Increased serotonin levels were found in the hippocampus and prefrontal cortex of the rats, an indicator of predictive validity. Vortioxetine passed through clinical trials with the help of a second company, Takeda, and has been approved in the US and Europe since 2013.
Although the drug was not approved by the FDA until 2013, patents for the chemical appeared in the US as early as 2000. International patents can be seen the following year. The lineage of this compound can be traced to a previous 1980 patent referencing azacycloalkanes and their derivatives for use as antidepressants. Lundbeck most likely incorporated these compounds into their database based on this information, and subsequently filed a patent of their own after synthesizing a salt incorporating one such compound. The rights to Vortioxetine and three other compounds were shared with Takeda when the companies entered a partnership to survive clinical trials. Takeda is a pharmaceutical company based in Tokyo who boast a $10+ million annual revenue. Lundbeck, founded in Copenhagen, has grown to become a $17.2 billion company. As part of their agreement, Lundbeck took over sales operations in the US while Takeda marketed in East Asia.
Vortioxetine, like other selective serotonin reuptake inhibitors (SSRIs), increases serotonin levels in the brain. It does this by inhibiting serotonin reuptake from the synapse and by binding with various serotonin receptors along the synapse. This is mostly effective for the treatment of MDD and other psychological disorders, but the higher levels of serotonin wear down the synaptic receptors which can lead to serotonin syndrome. This is where the neurons lose sensitivity to serotonin, reducing the effectiveness of the antidepressant and potentially worsening the symptoms. The ability of Vortioxetine to modulate receptors through both agonistic and antagonistic responses seems to eliminate the loss of sensitivity. Antagonism of serotonin receptors 5-HT3, 5-HT1D, and 5-HT7 contribute to the elevated levels, but agonism of the 5-HT1A receptor on the presynaptic neuron negates the negative feedback loop triggered by the increase in serotonin. Additionally, this may accelerate the antidepressant effect. This combination maintains the reuptake inhibition without wearing down the receptors that normally process the neurotransmitter.
The development of Vortioxetine moved quickly after clinical trials. It was branded as Brintellix, rebranded as Trintellix, and had success in multiple countries. This rebranding was approved by the FDA in July of 2015. This change was necessitated by a popular blood thinner by the name of Brillinta. An official safety announcement was made by the FDA regarding the change, alerting healthcare professionals and patients to be cautious when prescribing or taking these medications. It was recommended the generic name be included with prescriptions and packaging to avoid confusion. This change resulted in the chemical receiving a new National Drug Code number.
The active ingredient is delivered by film-coated tablets labeled by color depending on the dosage. The drug should not be taken with other serotonergic medications. Adverse reactions were uncommon, and ranged from mild effects such as nausea, headache, and dry mouth, up to more serious effects such as hypertensive crisis, increase rate of suicide, and pancreatitis. Although the drug occasionally produced adverse side effects, the improvement in effectiveness and longevity of the treatment made the drug a success.
The most compelling aspect of Vortioxetine’s development was the company’s decision to screen for a compound with multiple target interactions. They were able to discover a novel mechanism of treatment that improved both effectiveness of the medication and understanding of the disease.

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1 comment:

  1. What is the size of the market (in dollars)? Are there any recent new patents for combination drugs or new formulations? Any warning letters for current manufacturers?

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