Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo.
Department of Life Sciences and Health, Oslo Metropolitan University; and.
Ther Drug Monit. 2023 Oct 1;45(5):683-688. doi: 10.1097/FTD.0000000000001096. Epub 2023 Mar 30.
Paroxetine is a selective serotonin reuptake inhibitor metabolized by cytochrome P450 (CYP)2D6. Only small-scale studies have reported the impact of CYP2D6 genotype on paroxetine exposure, and international guidelines differ in their recommendations on whether paroxetine should be administered according to CYP2D6 genotype. To clarify this issue, the aim of the present study was to investigate the impact of CYP2D6 genotype on paroxetine serum concentration in a large population of patients after adjusting for CYP2C19 genotype, age, and sex.
Patients from a therapeutic drug monitoring database with records on their paroxetine serum concentrations and CYP2D6 and CYP2C19 genotyping between 2010 and 2021 were included in the study. The impact of CYP2D6 and CYP2C19 genotypes, age, and sex on the paroxetine concentration-to-dose (C/D) ratio was investigated by multiple linear regression analysis. Patients treated with relevant CYP inhibitors or inducers were excluded.
In total, 304 patients were included in the study: 17 CYP2D6 poor metabolizers (PMs), 114 intermediate metabolizers (IMs), 168 extensive metabolizers (EMs), and 5 ultrarapid metabolizers. Multiple linear regression analysis showed that CYP2D6 IMs and PMs had 2.2-fold and 3.8-fold higher paroxetine C/D-ratios than extensive metabolizers, respectively ( P < 0.001). Patients who were CYP2C19 IMs (n = 70) or PMs (n = 13) had 1.6-fold higher paroxetine C/D ratio than extensive metabolizers ( P = 0.04). An age ≥65 years was associated with a 2.9-fold increased C/D ratio ( P < 0.001), whereas sex was not significantly associated with paroxetine exposure.
The present study showed that CYP2D6 genotype is of significant importance for paroxetine dose adjustments. For CYP2D6 PMs, 25% of the regular paroxetine starting dose may be sufficient, whereas CYP2D6 IMs could receive 50% of the regular dosage. This well-powered study shows that the guidelines should consider the importance of CYP2D6 genotype for personalized dosing of paroxetine.
帕罗西汀是一种通过细胞色素 P450（CYP）2D6 代谢的选择性 5-羟色胺再摄取抑制剂。只有小规模的研究报告了 CYP2D6 基因型对帕罗西汀暴露的影响，国际指南在是否应根据 CYP2D6 基因型给予帕罗西汀的建议上存在差异。为了澄清这个问题，本研究旨在调查 CYP2D6 基因型对大样本患者帕罗西汀血清浓度的影响，同时调整了 CYP2C19 基因型、年龄和性别因素。
本研究纳入了 2010 年至 2021 年间接受治疗药物监测并记录了帕罗西汀血清浓度和 CYP2D6、CYP2C19 基因型的患者。采用多元线性回归分析研究 CYP2D6 和 CYP2C19 基因型、年龄和性别对帕罗西汀浓度与剂量（C/D）比值的影响。排除了接受相关 CYP 抑制剂或诱导剂治疗的患者。
共纳入 304 例患者：17 例 CYP2D6 弱代谢者（PMs）、114 例中间代谢者（IMs）、168 例广泛代谢者（EMs）和 5 例超快代谢者。多元线性回归分析显示，CYP2D6 IMs 和 PMs 的帕罗西汀 C/D 比值分别比广泛代谢者高 2.2 倍和 3.8 倍（P<0.001）。CYP2C19 IMs（n=70）或 PMs（n=13）患者的帕罗西汀 C/D 比值比广泛代谢者高 1.6 倍（P=0.04）。年龄≥65 岁与 C/D 比值增加 2.9 倍相关（P<0.001），而性别与帕罗西汀暴露无显著相关性。
本研究表明 CYP2D6 基因型对帕罗西汀剂量调整具有重要意义。对于 CYP2D6 PMs，常规帕罗西汀起始剂量的 25%可能就足够了，而 CYP2D6 IMs 则可以接受常规剂量的 50%。这项有力的研究表明，指南应考虑 CYP2D6 基因型对帕罗西汀个体化剂量的重要性。
