Estimating the <i>In Vivo</i> Function of <i>CYP2D6</i> Alleles through Population Pharmacokinetic Modeling of Brexpiprazole

Frederiksen, Trine; Areberg, Johan; Raoufinia, Arash; Schmidt, Ellen; Stage, Tore Bjerregaard; Brøsen, Kim

doi:10.1002/cpt.2791

Cited by 7 publications

(16 citation statements)

References 29 publications

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“…In the three original CYP2D6 genotype–phenotype analyses of brexpiprazole, tedatioxetine, and vortioxetine, considerable differences were found in the enzyme activity associated with different CYP2D6 decreased function alleles. These analyses showed consistently lower CYP2D6 activity for the CYP2D6*17 and *41 alleles compared to CYP2D6*10 8–10 . Therefore, when assessing genotype groups involving decreased function alleles, the interethnic differences observed might be a consequence of allele‐specific differences in CYP2D6 activity, as allele frequencies vary between ethnic groups.…”

Section: Discussionmentioning

confidence: 90%

“…CYP2D6 genotype information was available for 496 subjects. For details on the CYP2D6 genotyping assay, please refer to the original report 10 …”

Section: Methodsmentioning

confidence: 99%

“…For details on the CYP2D6 genotyping assay, please refer to the original report. 10 A PopPK model describing the joint PK of brexpiprazole and two of its metabolites, DM-3411 (major metabolite) and DM-3412 (minor metabolite), was developed based on more than 8000 plasma samples. The model included central and peripheral compartments for brexpiprazole and DM-3412 and a central compartment for DM-3411.…”

Section: How Might This Change Clinical Pharmacology or Translational...mentioning

confidence: 99%

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Does ethnicity impact CYP2D6 genotype–phenotype relationships?

Frederiksen

Areberg

Schmidt

et al. 2023

Clinical Translational Sci

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Polymorphism 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Substantial interindividual variability in CYP2D6 activity exists which is largely explained by genetic polymorphism. It has been hypothesized that other factors, such as ethnicity, may also contribute to the variability.

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Section: Discussionmentioning

confidence: 90%

“…CYP2D6 genotype information was available for 496 subjects. For details on the CYP2D6 genotyping assay, please refer to the original report 10 …”

Section: Methodsmentioning

confidence: 99%

Section: How Might This Change Clinical Pharmacology or Translational...mentioning

confidence: 99%

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Does ethnicity impact CYP2D6 genotype–phenotype relationships?

Frederiksen

Areberg

Schmidt

et al. 2023

Clinical Translational Sci

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“…In three recent studies, popPK meta‐analyses based on data from clinical studies of vortioxetine, 25 tedatioxetine 26 and brexpiprazole 27 were performed. The three compounds are all metabolized by CYP2D6 , and schematics of their biotransformation are presented in Figure 1.…”

Section: Using Poppk To Estimate Cyp2d6 Functionmentioning

confidence: 99%

“…In the three popPK‐based studies, a total of 80 CYP2D6*9 carriers were included in the analyses in total, resulting in the following activity value estimates: 0.22 (n = 39, vortioxetine), 25 0.46 (n = 21, tedatioxetine) 26 and 0.23 (n = 20, brexpiprazole) 27 . Whereas the results from the vortioxetine and brexpiprazole analyses support lowering the activity value for CYP2D6*9 , the tedatioxetine results suggest that a value of 0.5 may capture the phenotype appropriately.…”

Section: Using Poppk To Estimate Cyp2d6 Functionmentioning

confidence: 99%

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

Frederiksen

2023

Basic Clin Pharma Tox

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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.

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Comparison of brexpiprazole, aripiprazole, and placebo for Japanese major depressive disorder: A systematic review and network meta‐analysis

Kishi,

Sakuma,

Saito

et al. 2024

Neuropsychopharm Rep

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AimThis systematic review and frequentist network meta‐analysis used random‐effects models is conducted to determine whether there are differences in the efficacy, acceptability, tolerability, and safety profiles of brexpiprazole (BRE) and aripiprazole (ARI) for Japanese with major depressive disorder (MDD) who were inadequately responsive to antidepressants.MethodsOutcome measures were scores on the Montgomery Åsberg Depression Rating Scale (primary), the Clinical Global Impression severity scale, and social functioning scale; the non‐response rate; the non‐remission rate; all‐cause discontinuation; discontinuation due to adverse events (DAE); at least one adverse event (1AE); serious adverse event, akathisia; tremor; weight gain.ResultsA literature search identified three double‐blind, randomized, placebo‐controlled trials. These comprised one BRE study (with a 1 mg/day [BRE1] and a 2 mg/day [BRE2]) and two ARI studies (with a 3 mg/day arm and a flexible‐dose arm[within the dosage range approved in Japan]) (n = 1736). Both BRE and ARI demonstrated better efficacy than the placebo. BRE but not ARI had a higher DAE than the placebo. ARI but not BRE had a higher 1AE than the placebo. BRE and ARI had a higher risk of akathisia and weight gain than the placebo. There were no significant differences between BRE and ARI for any of the outcomes. Although BRE1 had good efficacy, it carried risk of weight gain. Although BRE2 also had efficacy, it carried risks of DAE, akathisia, and weight gain. However, the risk of akathisia in BRE2 was reduced by an initial dose of 0.5 mg/day rather than 1.0 mg/day.ConclusionsOverall BRE showed similar utility to ARI and a good risk–benefit balance.

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Estimating the In Vivo Function of CYP2D6 Alleles through Population Pharmacokinetic Modeling of Brexpiprazole

Cited by 7 publications

References 29 publications

Does ethnicity impact CYP2D6 genotype–phenotype relationships?

Does ethnicity impact CYP2D6 genotype–phenotype relationships?

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

Comparison of brexpiprazole, aripiprazole, and placebo for Japanese major depressive disorder: A systematic review and network meta‐analysis

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