Pharmacodynamics + Activities of<unk>  at human molecular targets Target Affinity Functional activity Action Ki (nM) IC50 / EC50 (nM) IA (%) 1.6 5.4 – Inhibition 113 – – Inhibition 5-HT1A 15 200 96 Agonist 5-HT1B 33 120 55 Partial agonist 5-HT1D 54 370 – Antagonist 5-HT2C 180 – – – 5-HT3A 3.7 12 – Antagonist 5-HT7 19 450 – Antagonist β1-adr. 46 – – – Note: No significant activities at 70 other molecular targets (>1,000 nM) (including e.g. the ). Sources:<unk>  increases serotonin concentrations in the brain by inhibiting its reuptake in the synapse, and also modulates (activates or blocks) certain serotonin receptors. This puts it in the class of serotonin modulators and stimulators, which also includes vilazodone. More specifically,<unk>  is a serotonin reuptake inhibitor, agonist of the serotonin 5-HT1A receptor, partial agonist of the 5-HT1B receptor, and antagonist of the serotonin 5-HT1D, 5-HT3, and 5-HT7 receptors, as well as an apparent ligand of the β1-adrenergic receptor. In terms of functional activity however,<unk>  appears to be much more potent on serotonin reuptake inhibition and 5-HT3 receptor antagonism than for its interactions with the other serotonin receptors. Whereas<unk>  has IC50 or EC50 values of 5.4 nM for the SERT and 12 nM for the 5-HT3 receptor, its values are 120 to 450 nM for the 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT7 receptors. This translates to about 22- to 83-fold selectivity for SERT inhibition and 10- to 38-fold selectivity for 5-HT3 antagonism over activities at the other serotonin receptors. It has been claimed that the serotonin transporter (SERT) and 5-HT3 receptor may be primarily occupied at lower clinical doses of<unk>  and that the 5-HT1B, 5-HT1A, and 5-HT7 receptors may additionally be occupied at higher doses. Occupancy of the serotonin transporter with<unk>  in young men was found to be highest in the raphe nucleus with median occupancies of 25%, 53%, and 98% after 9 days of administration with 2.5, 10, and 60 mg/day<unk> . In another study, serotonin transporter occupancy in men was 50%, 65%, and ≥80% for 5, 10, and 20 mg/day<unk> . Based on its clinical efficacy (e.g., at 5 mg/day), it appears that<unk>  may produce antidepressant effects at SERT occupancy as low as 50%. This is in apparent contrast to SSRIs and SNRIs, which appear to require a minimum of 70 to 80% occupancy for antidepressant efficacy. These findings are suggestive that the antidepressant effects of<unk>  may be mediated by serotonin receptor interactions in addition to serotonin reuptake inhibition. A study found no significant occupancy of the 5-HT1A receptor with<unk>  at 30 mg/day for 9 days, which suggests that at least this specific serotonin receptor may not be involved in the clinical pharmacology of<unk> . However, methodological concerns were noted that may limit the interpretability of this result. Occupancy of other serotonin receptors like 5-HT3 and 5-HT7 by<unk>  in humans does not seem to have been studied. In relation to the preceding, the contribution of serotonin receptor interactions to the antidepressant effects of<unk>  is unknown and remains to be established. Uncertainties remain about whether<unk>  is indeed a clinically multimodal antidepressant or whether it is effectively "just another selective serotonin reuptake inhibitor". Antagonism of the 5-HT3 receptor has been found to enhance the increase in brain serotonin levels produced by serotonin reuptake inhibition in animal studies. Whether or not the 5-HT3 receptor antagonism of<unk>  likewise does this in humans or contributes to its clinical antidepressant efficacy is unclear. SSRIs and 5-HT1A receptor agonists often produce nausea as a side effect, whereas 5-HT3 receptor antagonists like ondansetron are antiemetics and have been found to be effective in treating SSRI-induced nausea. It was thought that the 5-HT3 receptor antagonism of<unk>  would reduce the incidence of nausea relative to SSRIs. However, clinical trials found significant and dose-dependent rates of nausea with<unk>  that appeared to be comparable to those with the SNRI duloxetine. Pharmacokinetics<unk>  levels after a single 10 mg oral dose of<unk>  in 18 fasted and 18 fed healthy Japanese adults. Simulation of<unk>  levels and accumulation with 10 mg/day oral<unk>  plus a 17 mg intravenous bolus of<unk>  versus 10 mg/day oral<unk>  alone.<unk>  is well-absorbed when taken orally and has an oral bioavailability of 75%. It is systemically detectable after a single oral dose by 0.781 hours. Peak levels of<unk>  are reached within 7 to 11 hours post-dose with single or multiple doses. Steady-state levels of<unk>  are generally reached within 2 weeks of administration, with 90% of individuals reaching 90% of steady state after 12 days of administration. Steady-state peak levels of<unk>  with doses of 5, 10, and 20 mg/day were 9, 18, and 33 ng/mL, respectively. The accumulation index of<unk>  (area-under-the-curve levels after a single dose versus at steady state) is 5 to 6. A loading dose given intravenously has been found to achieve steady-state levels more rapidly with oral<unk>  therapy. The pharmacokinetics of<unk>  are known to be linear and dose proportional over a range of 2.5 to 75 mg for single doses and 2.5 to 60 mg for multiple doses. Food has no influence on the pharmacokinetics of<unk> . The apparent volume of distribution of<unk>  is large and ranges from 2,500 to 3,400 L after single or multiple doses of 5 to 20 mg<unk> , with extensive extravascular distribution. The plasma protein binding of<unk>  is approximately 98 or 99%, with about 1.25 ± 0.48% free or unbound.<unk>  is extensively metabolized by oxidation via cytochrome P450 enzymes and subsequent glucuronidation via UDP-glucuronosyltransferase. CYP2D6 is the primary enzyme involved in the metabolism of<unk> , but others including CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 are also involved. It is also metabolized by alcohol dehydrogenase, aldehyde dehydrogenase, and aldehyde oxidase. Six metabolites of<unk>  have been identified. The major metabolite of<unk>  (Lu AA34443) is inactive and its minor active metabolite (Lu AA39835) is not thought to cross the blood–brain barrier. The remaining metabolites are glucuronide conjugates. Hence,<unk>  itself is thought to be primarily responsible for its pharmacological activity. The estimated total clearance of<unk>  ranges from 30 to 41 L/h. The elimination half-life of<unk>  is 66 hours, with a range of 59 to 69 hours after single or multiple doses. Elimination of<unk>  is almost entirely via the liver (99%) rather than the kidneys (<1%). Approximately 85% of<unk>  was recovered in a single-dose excretion study after 15 days, with 59% in urine and 26% in feces. Pharmacogenomics Genetic variations in cytochrome P450 enzymes can influence exposure to<unk> . CYP2D6 extensive metabolizers have approximately 2-fold higher clearance of<unk>  than CYP2D6 poor metabolizers. The estimated clearance rates were 52.9, 34.1, 26.6, and 18.1 L/h for CYP2D6 ultra-rapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers. Area-under-the-curve levels of<unk>  were 35.5% lower in CYP2D6 ultra-rapid metabolizers than in extensive metabolizers, though with significant overlap due to interindividual variability. Dosage adjustment for CYP2D6 ultra-rapid metabolizers is considered to not be necessary.<unk>  exposure in CYP2D6 poor metabolizers is expected to be approximately twice as high as in extensive metabolizers. Depending on the individual response, dosage adjustment may be considered for CYP2D6 poor metabolizers, with a maximum recommended dosage of 10 mg/day for known such individuals. In addition to CYP2D6, CYP2C19 extensive metabolizers have 1.4-fold higher clearance of<unk>  than poor metabolizers. However, this is not considered to be clinically important and dose adjustment is not considered to be necessary based on CYP2C19 status.
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