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Thursday, 27 January 2011

New Drug Approvals 2011 - Pt. II Vilazodone hydrochloride (ViibrydTM)

ATC code (partial): N06A

On January 21st 2011, the FDA approved Vilazodone hydrochloride for the treatment of major depressive disorder (MDD) (research code: EMD-68843, tradename:Viibryd) (NDA 022567). MDD is a mental disorder believed to arise from abnormal levels of neurotransmitters (primarily serotonin) in the central nervous system. Symptoms are of broad spectrum and typically include depressed mood, fatigue, change of appetite and weight and suicidal thoughts, or attempted suicide. There are already a large number of therapeutics available for the treatment of MDD including the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (ChEMBL41), sertraline (ChEMBL809), paroxetine (CHEMBL569172) and more recently escitalopram (CHEMBL1508). A number of other mechanisms have been explored for treatment of depression, including drugs such as against the serotonin receptor 5HT1A - such as buspirone (research code:BMS-528215, tradename:BuSpar)CHEMBL49) and flesinoxan (clinical trial phase only). Vilazodone however is the first SSRI that also is a partial agonist of 5TH1A (and as such show designed and intended polypharmacology).

Brain function relies on the transmission and regulation of excitatory and inhibitory signals at the synapses of nerve cells. Upon activation, a presynaptic neuron releases neurotransmitters into the synaptic cleft which in turn activate or inhibit the postsynaptic neuron by binding specific receptors. One of the neurotransmitters with excitatory effects is the biogenic amine serotonin (CHEMBL39, CHEBI:28790). After its release from the presynaptic neuron, Serotonin transmits an excitatory signal and is then removed from the synaptic cleft by an uptake mechanism involving the sodium dependent serotonin transporter (SERT) (Ki 0.1nM Uniprot:P31645 Pfam:PF00209). SERT is a member of a very important family of drug targets including the analogous norepinephrine transporter, other pharmacologically important ligands that have related transporters include GABA, dopamine, amino-acids and so forth) Vilazodone is selective for serotonin over the norepinephrine (Ki 56 nM UniProt:P23975) and dopamine transporters (Ki 37 nM UniProt:Q01959). Inhibition of serotonin reuptake with SSRIs leads to increased levels of serotonin in the synaptic cleft and is used in the treatment of MDD to compensate for the lower homeostatic levels of serotonin in MDD patients compared to healthy individuals. The exact mechanism by which this helps MDD patients is not clear but involves long-term desensitization of presynaptic serotonin receptors which are part of a negative feedback loop in the biosynthesis of serotonin. In addition to it's effects as an SSRI, Vilazodone is a partial agonist of the 5HT1A receptor (IC50 2.1 nM, Uniprot:P08908, Pfam:PF00001, ChEMBL:214) (and selective over the related 5-HT1D, 5-HT2A, and 5-HT2C receptors). However the net result of this partial action on serotonergic transmission and its role in Vilazodone’s overall antidepressant effect are unclear. The 5HT1A receptor is a rhodopsin-like G-protein-coupled receptor (GPCR), the largest single family of historically successful drug targets.

Vilazodone (IUPAC: 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide
InChI: 1S/C26H27N5O2/c27-16-18-4-6-23-22(13-18)19(17-29-23)3-1-2-8-30-9-11-31(12-10-30)21-5-7-24-20(14-21)15-25(33-24)26(28)32/h4-7,13-15,17,29H,1-3,8-12H2,(H2,28,32)
SMILES: NC(=O)c1oc2ccc(cc2c1)N3CCN(CCCCc4c[nH]c5ccc(cc45)C#N)CC3 ChemSpider: 5293518 Chembl:439849) is a synthetic organic molecule with no chiral centers and a molecular weight of 441.5 Da (for the free base) and a calculated LogP of 4.54. With 7 hydrogen bond acceptors and two hydrogen bond donors it is therefore fully compliant with the Lipinski Rule of five. The 7 rotatable bonds make Vilazodone a rather flexible compound. The physical chemistry will be dominated by the basic center in the piperazine ring.

The pharmacology of Vilazodone is largely due to the parent, dosed drug, and due to the long terminal half life of 25 hr (elimination is largely hepatic), steady state plasma levels are reached after about three days. The mean Cmax value is 156 ng/mL, and the mean AUC (0-24 hours) value is 1645 ng·h/mL. Tmax is around 4.5 hr post administration. Vilazodone is widely distributed and approximately 96-99% protein-bound. Vilazodone is extensively metabolized in the liver through CYP and non-CYP pathways with major contributions from CYP3A4 (Uniprot Id: P08684). The non-CYP route is believed to open via liver carboxylesterase (Uniprot Id: P23141). The absolute bioavailability of vilazodone is 72% with food - Vilazodone shows a large food effect, and if taken without food, bioavailability is significantly lower.

Vilazodone is administered orally at a typical dose of 40 mg once daily (equivalent to a daily dose of ~83.6 uM of Vilazodone). At start of therapy, the drug is titrated, starting with 10mg once daily over the course of seven days followed by 20 mg once daily over another 7 days before the full dose of 45 mg per day is administered.

Many drugs of this general class have inherent safety issues, and Vilazodone has safety risks associated with the induction of suicidal thoughts in young adults, adolescents and children. Vilazodone is not approved for the treatment of depressive disorders in children. Viibryd has a boxed warning.

The full prescribing information is found for Vilazodone here.

The license holder is Clinical Data and the product website is

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