دورية أكاديمية
Estimating the In Vivo Function of CYP2D6 Alleles through Population Pharmacokinetic Modeling of Brexpiprazole.
| العنوان: | Estimating the In Vivo Function of CYP2D6 Alleles through Population Pharmacokinetic Modeling of Brexpiprazole. |
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| المؤلفون: | Frederiksen T; Department of Experimental Medicine, H. Lundbeck A/S, Valby, Denmark.; Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark., Areberg J; Department of Experimental Medicine, H. Lundbeck A/S, Valby, Denmark., Raoufinia A; Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, Maryland, USA., Schmidt E; Department of Experimental Medicine, H. Lundbeck A/S, Valby, Denmark., Stage TB; Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark., Brøsen K; Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark. |
| المصدر: | Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2023 Feb; Vol. 113 (2), pp. 360-369. Date of Electronic Publication: 2022 Nov 29. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley Country of Publication: United States NLM ID: 0372741 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-6535 (Electronic) Linking ISSN: 00099236 NLM ISO Abbreviation: Clin Pharmacol Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2015- : Hoboken, NJ : Wiley Original Publication: St. Louis : C.V. Mosby |
| مواضيع طبية MeSH: | Cytochrome P-450 CYP2D6*/genetics , Cytochrome P-450 CYP2D6*/metabolism , Serotonin Agents*/pharmacokinetics , Dopamine Agonists*/pharmacokinetics, Alleles ; Genotype ; Phenotype ; Humans |
| مستخلص: | Accurate prediction of CYP2D6 phenotype from genotype information is important to support safe and efficacious pharmacotherapy with CYP2D6 substrates. To facilitate accurate CYP2D6 genotype-phenotype translation, there remains a need to investigate the enzyme activity associated with individual CYP2D6 alleles using large clinical data sets. This study aimed to quantify and compare the in vivo function of different CYP2D6 alleles through population pharmacokinetic (PopPK) modeling of brexpiprazole using data from 13 clinical studies. A PopPK model of brexpiprazole and its two metabolites, DM-3411 and DM-3412, was developed based on plasma concentration samples from 826 individuals. As the minor metabolite, DM-3412, is formed via CYP2D6, the metabolic ratio of DM-3412:brexpiprazole calculated from the PopPK parameter estimates was used as a surrogate measure of CYP2D6 activity. A CYP2D6 genotype-phenotype analysis based on 496 subjects showed that the CYP2D6*2 allele (n = 183) was associated with only 10% enzyme activity relative to the wild-type allele (CYP2D6*1) and a low enzyme activity was consistently observed across genotypes containing CYP2D6*2. Among the decreased function alleles, the following enzyme activities relative to CYP2D6*1 were estimated: 23% for CYP2D6*9 (n = 20), 32% for CYP2D6*10 (n = 62), 64% for CYP2D6*14 (n = 1), 4% for CYP2D6*17 (n = 37), 4% for CYP2D6*29 (n = 13), and 9% for CYP2D6*41 (n = 64). These findings imply that a lower functional value would more accurately reflect the in vivo function of many reduced function CYP2D6 alleles in the metabolism of brexpiprazole. The low enzyme activity observed for CYP2D6*2, which has also been reported by others, suggests that the allele exhibits substrate-specific enzyme activity. (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.) |
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| المشرفين على المادة: | 2J3YBM1K8C (brexpiprazole) EC 1.14.14.1 (Cytochrome P-450 CYP2D6) 0 (Serotonin Agents) 0 (Dopamine Agonists) |
| تواريخ الأحداث: | Date Created: 20221109 Date Completed: 20230127 Latest Revision: 20230415 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC10099095 |
| DOI: | 10.1002/cpt.2791 |
| PMID: | 36350097 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1532-6535 |
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| DOI: | 10.1002/cpt.2791 |