Tedatioxetine
Tedatioxetine is an experimental antidepressant developed by H. Lundbeck A/S for the treatment of major depressive disorder and generalized anxiety disorder. It acts as a triple reuptake inhibitor with preference for serotonin and norepinephrine over dopamine, and as an antagonist at 5-HT2A, 5-HT2C, 5-HT3, and α1A-adrenergic receptors. In 2007 Lundbeck and Takeda entered into a partnership that included tedatioxetine but was focused on another, more advanced Lundbeck drug candidate, vortioxetine.
Tedatioxetine reached Phase II clinical trials for major depressive disorder in 2009 but was discontinued in May 2016, with no further development reported. Despite its termination, data from clinical studies have provided valuable insights into CYP2D6 metabolism and pharmacogenetics.
Pharmacology
Pharmacokinetics
Tedatioxetine is a sensitive substrate of the CYP2D6 enzyme, exhibiting significant interindividual variability in metabolism due to genetic polymorphisms. A 2021 population pharmacokinetic study involving 578 subjects quantified CYP2D6 activity across genotypes, reporting mean oral clearances of 18 L/h for poor metabolizers, 40 L/h for intermediate metabolizers, 60 L/h for normal metabolizers, and 77 L/h for ultrarapid metabolizers. Approximately 80% of clearance is mediated by CYP2D6.The drug has a slow absorption rate, with a median time to maximum plasma concentration of 5–6 hours. Its primary metabolite, Lu AA37208, shows a similar or shorter tmax, indicating presystemic metabolism. The study highlighted low enzyme activity for CYP2D6*17 and *41 alleles, suggesting a need to revise activity scores for personalized dosing.
CYP2D6 variability posed challenges for consistent dosing across populations, particularly for CYP2D6*17 and *41 carriers.
Pharmacodynamics
Tedatioxetine is a multimodal antidepressant that inhibits the reuptake of serotonin, norepinephrine, and dopamine, with a preference for serotonin and norepinephrine. It also antagonizes 5-HT2A, 5-HT2C, and 5-HT3 serotonin receptors and α1A-adrenergic receptor antagonist, potentially enhancing monoamine transmission and reducing side effects like nausea associated with 5-HT3 activation.Preclinical studies suggest this profile may improve efficacy in MDD by targeting multiple neurotransmitter systems.
The compound’s receptor antagonism, particularly at 5-HT2C and 5-HT3, may contribute to its anxiolytic properties, making it a candidate for GAD treatment. Its triple reuptake inhibition distinguishes it from selective serotonin reuptake inhibitors, potentially offering broader symptom relief in complex mood disorders.
Clinical development
Tedatioxetine was discovered by Lundbeck and entered a partnership with Takeda Pharmaceutical Company in 2007, alongside the more advanced candidate vortioxetine. By 2009, tedatioxetine had progressed to Phase II clinical trials for MDD, demonstrating promising efficacy and safety in preliminary studies. However, Lundbeck and Takeda prioritized vortioxetine, which gained regulatory approval, leading to tedatioxetine’s removal from Lundbeck’s pipeline by August 2013. On 10 May 2016, all development was officially discontinued.A Chinese patent indicates interest in tedatioxetine’s synthesis outside Lundbeck, suggesting potential for further research, though no active development has been reported. The discontinuation reflects the competitive MDD market, with patent expiries for drugs like Cymbalta and Abilify and the launch of vortioxetine in 2014.