The primary purpose of this study is to assess the efficacy in treating patients with Major Depressive Disorder of one or more doses of Lu AA24530 relative to placebo

Start Date01 Oct 2007

Sponsor / Collaborator

H. Lundbeck A/S

100 Clinical Results associated with Tedatioxetine

100 Translational Medicine associated with Tedatioxetine

100 Patents (Medical) associated with Tedatioxetine

Literatures (Medical) associated with Tedatioxetine

01 Aug 2023·Basic & clinical pharmacology & toxicology

Using population pharmacokinetic analyses of drugs metabolized by CYP2D6 to study the genotype-phenotype translation.

Review

Author: Frederiksen, Trine

Cytochrome P450 2D6 (CYP2D6) is an important drug-metabolizing enzyme exhibiting extensive interindividual variability predominantly caused by genetic polymorphism. Predicting CYP2D6 function based on genotype may be used to personalize pharmacotherapy, but the process of translating CYP2D6 genotype into predicted phenotype is complex and has suffered from a lack of consensus. The Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group have proposed a standardized translation scheme based on the activity score system aiming to facilitate more consistent CYP2D6 genotype-phenotype translation. However, this system remains suboptimal particularly with regards to decreased function alleles and substrate-specific behaviour. This review summarizes the process and challenges for functional assignment of CYP2D6 alleles. We discuss population pharmacokinetics (popPK) as a tool for estimating CYP2D6 function and present findings from three popPK meta-analyses quantifying the impact of individual CYP2D6 alleles in the metabolism of vortioxetine, tedatioxetine and brexpiprazole. Findings from these analyses indicate that the activity values currently assigned to decreased function alleles CYP2D6*9, *17 and *41 overestimate their function. Moreover, the CYP2D6*2 allele exhibited reduced activity in the metabolism of brexpiprazole, indicating substrate-specific behaviour. Considering the totality of the evidence, the activity score system may be further refined to better reflect the enzyme function associated with these alleles.

01 Jun 2023·Clinical and Translational Science

Does ethnicity impact CYP2D6 genotype–phenotype relationships?

Article

Author: Brøsen, Kim ; Frederiksen, Trine ; Schmidt, Ellen ; Stage, Tore Bjerregaard ; Areberg, Johan

AbstractPolymorphism of the CYP2D6 gene leads to substantial interindividual variability in CYP2D6 enzyme activity. Despite improvements in prediction of CYP2D6 activity based on genotype information, large interindividual variability within CYP2D6 genotypes remains and ethnicity could be a contributing factor. The aim of this study was to investigate interethnic differences in CYP2D6 activity using clinical datasets of three CYP2D6 substrates: (i) brexpiprazole (N = 476), (ii) tedatioxetine (N = 500), and (iii) vortioxetine (N = 1073). The CYP2D6 activity of all individuals in the dataset was estimated through population pharmacokinetic analyses as previously reported. Individuals were assigned a CYP2D6 phenotype and CYP2D6 genotype group based on their CYP2D6 genotype and interethnic differences were investigated within each group. Among individuals categorized as CYP2D6 normal metabolizers, African Americans had a lower CYP2D6 activity compared to Asians (p < 0.01) and in the tedatioxetine and vortioxetine analyses also compared to Whites (p < 0.01). Among CYP2D6 intermediate metabolizers, interethnic differences were also observed, but the findings were not consistent across the substrates. Asian carriers of CYP2D6 decreased function alleles tended to exhibit higher CYP2D6 activity compared to Whites and African Americans. The observed interethnic differences within the CYP2D6 phenotype and genotype groups appeared to be driven by differences in CYP2D6 allele frequencies across ethnicities rather than interethnic differences in enzyme activity for individuals carrying identical CYP2D6 genotypes.

01 Sep 2021·CPT: Pharmacometrics & Systems PharmacologyQ3 · MEDICINE

Cytochrome P450 2D6 genotype–phenotype characterization through population pharmacokinetic modeling of tedatioxetine

Q3 · MEDICINE

ArticleOA

Author: Schmidt, Ellen ; Brøsen, Kim ; Frederiksen, Trine ; Stage, Tore Bjerregaard ; Areberg, Johan

AbstractThe cytochrome P450 (CYP) 2D6 enzyme exhibits large interindividual differences in metabolic activity. Patients are commonly assigned a CYP2D6 phenotype based on their CYP2D6 genotype, but there is a lack of consensus on how to translate genotypes into phenotypes, causing inconsistency in genotype‐based dose recommendations. The aim of this study was to quantify and compare the impact of different CYP2D6 genotypes and alleles on CYP2D6 metabolism using a large clinical data set. A population pharmacokinetic (popPK) model of tedatioxetine and its CYP2D6‐dependent metabolite was developed based on pharmacokinetic data from 578 subjects. The CYP2D6‐mediated metabolism was quantified for each subject based on estimates from the final popPK model, and CYP2D6 activity scores were calculated for each allele using multiple linear regression. The activity scores estimated for the decreased function alleles were 0.46 (CYP2D6*9), 0.34 (CYP2D6*10), 0.01 (CYP2D6*17), 0.65 (CYP2D6*29), and 0.21 (CYP2D6*41). The CYP2D6*17 and CYP2D6*41 alleles were thus associated with the lowest CYP2D6 activity, although only the difference to the CYP2D6*9 allele was shown to be statistically significant (p = 0.02 and p = 0.05, respectively). The study provides new in vivo evidence of the enzyme function of different CYP2D6 genotypes and alleles. Our findings suggest that the activity score assigned to CYP2D6*41 should be revisited, whereas CYP2D6*17 appears to exhibit substrate‐specific behavior. Further studies are needed to confirm the findings and to improve the understanding of CYP2D6 genotype–phenotype relationships across substrates.

100 Deals associated with Tedatioxetine

External Link

KEGG	Wiki	ATC	Drug Bank
D10170	Tedatioxetine	-	DB12641

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Discovery	France	H. Lundbeck A/S	01 Oct 2007
Depressive Disorder, Major	Discovery	Malaysia	H. Lundbeck A/S	01 Oct 2007
Depressive Disorder, Major	Discovery	Serbia	H. Lundbeck A/S	01 Oct 2007
Depressive Disorder, Major	Discovery	Sweden	H. Lundbeck A/S	01 Oct 2007
Depressive Disorder, Major	Discovery	Finland	H. Lundbeck A/S	01 Oct 2007
Depressive Disorder, Major	Discovery	Lithuania	H. Lundbeck A/S	01 Oct 2007
Depressive Disorder, Major	Discovery	Norway	H. Lundbeck A/S	01 Oct 2007
Depressive Disorder, Major	Discovery	Canada	H. Lundbeck A/S	01 Oct 2007
Depressive Disorder, Major	Discovery	Ukraine	H. Lundbeck A/S	01 Oct 2007
Depressive Disorder, Major	Discovery	India	H. Lundbeck A/S	01 Oct 2007

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