Department of Quantitative Clinical Pharmacology, Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 60015, USA.
Clinical and Quantitative Pharmacology, H. Lundbeck A/S, Copenhagen-Valby, Denmark.
Clin Pharmacokinet. 2018 Jun;57(6):673-686. doi: 10.1007/s40262-017-0612-7.
Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed. Vortioxetine is metabolized by cytochrome P450 enzymes and subsequently by uridine diphosphate glucuronosyltransferase. The major metabolite is pharmacologically inactive, and the minor pharmacologically active metabolite is not expected to cross the blood-brain barrier, making the parent compound primarily responsible for in-vivo activity. No clinically relevant differences were observed in vortioxetine exposure by sex, age, race, body size, and renal or hepatic function. Dose adjustment is only recommended for cytochrome P450 2D6 poor metabolizers based on polymorphism of the cytochrome P450 enzymes involved. Similarly, except for bupropion, a strong cytochrome P450 2D6 inhibitor, and rifampin, a broad cytochrome P450 inducer, co-administration of other drugs evaluated did not affect the vortioxetine exposure or safety profile in any clinically meaningful way. Pharmacodynamic studies demonstrated that vortioxetine achieved high levels of serotonin transporter occupancy in relevant brain areas, affected neurotransmitter levels in the cerebrospinal fluid, and modified abnormal resting state networks in the brain over the therapeutic dose range. Overall, vortioxetine can be administered in most populations studied to date without major dose adjustments; however, dose adjustments should be considered on a patient-by-patient basis.
文拉法辛是一种新型抗抑郁药，具有多种作用机制，目前已被批准用于治疗重度抑郁症。文拉法辛每天口服一次，剂量为 5-20 毫克。文拉法辛的药代动力学呈线性和剂量比例关系，平均终末半衰期约为 66 小时，一般在给药 2 周内达到稳态血浆浓度。文拉法辛的平均绝对口服生物利用度为 75%。未观察到食物对药代动力学的影响。文拉法辛主要通过细胞色素 P450 酶代谢，然后通过尿苷二磷酸葡萄糖醛酸转移酶代谢。主要代谢产物无药理活性，次要的药理活性代谢产物预计不会穿过血脑屏障，使母体化合物主要负责体内活性。在性别、年龄、种族、体型以及肾功能和肝功能方面，文拉法辛的暴露量没有观察到临床相关差异。根据参与的细胞色素 P450 酶的多态性，仅建议细胞色素 P450 2D6 弱代谢者调整剂量。同样，除了强效细胞色素 P450 2D6 抑制剂安非他酮和广泛的细胞色素 P450 诱导剂利福平外，其他评估的药物联合使用不会以任何有临床意义的方式影响文拉法辛的暴露量或安全性概况。药效学研究表明，文拉法辛在相关脑区达到了较高的 5-羟色胺转运体占有率，影响了脑脊液中的神经递质水平，并在治疗剂量范围内改变了大脑的异常静息状态网络。总的来说，迄今为止在大多数研究人群中都可以使用文拉法辛，而无需进行主要剂量调整；然而，应根据患者的具体情况考虑剂量调整。
