Frederiksen Trine, Areberg Johan, Schmidt Ellen, Bjerregaard Stage Tore, Brøsen Kim
Department of Experimental Medicine, H. Lundbeck A/S, Valby, Denmark.
Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Clin Pharmacol Ther. 2021 Jan;109(1):150-159. doi: 10.1002/cpt.1972. Epub 2020 Jul 27.
Assignment of CYP2D6 phenotype from genotype data can be challenging and despite efforts to standardize translation, there is currently no universally accepted method. To facilitate standardization, there remains a need to precisely quantify the in vivo function of different CYP2D6 genotypes. Vortioxetine is metabolized to its major metabolite, Lu AA34443, primarily via CYP2D6. The aim of this study was to quantify the in vivo CYP2D6 activity of different CYP2D6 alleles and genotypes through population pharmacokinetic (PopPK) modeling of vortioxetine and Lu AA34443. Plasma concentration data of vortioxetine and Lu AA34443 from 1,140 subjects originating from 29 clinical pharmacology studies were pooled for the analysis. A joint PopPK model described the pharmacokinetics of vortioxetine and Lu AA34443 simultaneously and provided estimates of the CYP2D6-mediated metabolism for each subject. Subjects normally classified as CYP2D6 intermediate metabolizers (IMs) showed different levels of CYP2D6 activity with carriers of one fully functional allele and one null function allele having 77% higher CYP2D6 activity compared with carriers of two decreased function alleles (P < 0.0001). The decreased function alleles were associated with different levels of reduction of CYP2D6 activity. Fixing the activity of fully functional alleles to 1.0, the relative activities of CYP2D69, CYP2D610, CYP2D617, and CYP2D641 were 0.22, 0.37, 0.17, and 0.21, respectively. The activity of CYP2D610 was shown to be significantly greater than that of CYP2D617 (P = 0.01) and CYP2D6*41 (P = 0.02). These results warrant further discussion of current CYP2D6 genotype-phenotype classification systems particularly regarding decreased function alleles and the IM phenotype.
根据基因型数据确定CYP2D6表型具有挑战性，尽管人们努力使翻译标准化，但目前尚无普遍接受的方法。为促进标准化，仍需要精确量化不同CYP2D6基因型的体内功能。伏硫西汀主要通过CYP2D6代谢为其主要代谢产物Lu AA34443。本研究的目的是通过伏硫西汀和Lu AA34443的群体药代动力学（PopPK）建模，量化不同CYP2D6等位基因和基因型的体内CYP2D6活性。汇总了来自29项临床药理学研究的1140名受试者的伏硫西汀和Lu AA34443血浆浓度数据进行分析。一个联合PopPK模型同时描述了伏硫西汀和Lu AA34443的药代动力学，并提供了每个受试者CYP2D6介导代谢的估计值。通常被归类为CYP2D6中间代谢者（IMs）的受试者表现出不同水平的CYP2D6活性，与携带两个功能降低等位基因的携带者相比，携带一个功能完全正常等位基因和一个无功能等位基因的携带者的CYP2D6活性高77%（P < 0.0001）。功能降低的等位基因与CYP2D6活性的不同降低水平相关。将功能完全正常等位基因的活性固定为1.0，CYP2D69、CYP2D610、CYP2D6* / 17和CYP2D641的相对活性分别为0.22、0.37、0.17和0.21。结果显示CYP2D610的活性显著高于CYP2D617（P = 0.01）和CYP2D641（P = 0.02）。这些结果值得对当前的CYP2D6基因型 - 表型分类系统进行进一步讨论，特别是关于功能降低的等位基因和IM表型。
