Vilazodone is mainly metabolized by cytochrome P450(CYP)3A4 and also to a minor extent by CYP2C19 and CYP 2D6. Although the metabolic pathway for vilazodone has not been fully studied, a proposed mechanism for metabolism in rats was published in 2017.
Viibryd is extensively metabolized through CYP and non-CYP pathways (possibly by carboxylesterase), with only 1% of the dose recovered in the urine and 2% of the dose recovered in the feces as unchanged vilazodone. CYP3A4 is primarily responsible for its metabolism among CYP pathways, with minor contributions from CYP2C19 and CYP2D6. In vitro studies with human microsomes and human hepatocytes indicate that vilazodone is unlikely to inhibit or induce the metabolism of other CYP (except for CYP2C8) substrates; and an in vivo study with probe substrates for CYP2C19, 2D6 and 3A4 showed vilazodone did not alter the pharmacokinetics of the probe substrates. However, an in vivo study with probe substrate for CYP2C19 demonstrated a minor induction of CYP2C19. Strong inhibitors of CYP3A4 (e.g., ketoconazole) can reduce the metabolism of vilazodone in vivo and increase exposure. Conversely, strong inducers of CYP3A4 (e.g., carbamazepine) can decrease vilazodone exposure.
IDENTIFICATION AND USE: Vilazodone is a white to off-white solid that is formulated into film-coated tablets. Vilazodone is a combined selective serotonin-reuptake inhibitor and serotonin type 1-A (5-hydroxytryptamine (5-HT1A) receptor partial agonist. It is used for the treatment of major depressive disorder in adults. HUMAN EXPOSURE AND TOXICITY: In clinical trials toxic effects of vilazodone at 200-280 mg included serotonin syndrome, lethargy, restlessness, hallucinations, and disorientation. Serotonin syndrome, a potentially life-threatening toxicity has also been reported at therapeutic doses. Serotonin syndrome symptoms may include mental status changes (agitation, hallucinations, delirium, and coma), autonomic instability (tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (nausea, vomiting, diarrhea). While serotonin syndrome has been reported during vilazodone monotherapy, it is a particular concern when used with other serotonergic drugs and with drugs that impair metabolism of serotonin (in particular, monamine oxidase inhibitors (MAOIs). The concomitant use of vilazdone with MAOIs intended to treat psychiatric disorders is contraindicated. Vilazodone is also not approved for use in pediatric patients. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors and others) showed that these drugs increase the risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Also, some neonates exposed to serotonegic antidepressants (including vilazodone) late in the third trimester of pregnancy have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. In some cases, the clinical picture is consistent with serotonin syndrome. Infants exposed to vilazodone in pregnancy may also have an increased risk for persistent pulmonary hypertension of the newborn, a rare heart and lung condition associated with substantial neonatal morbidity and mortality. ANIMAL STUDIES: Vilazodone caused some developmental toxicity in rats, but was not teratogenic in rats or rabbits. When vilazodone was administered to pregnant rats at an oral dose of 30 times the maximum recommended human dose during the period of organogenesis and throughout pregnancy and lactation, the number of live born pups was decreased. There was an increase in early postnatal pup mortality, and among surviving pups there was decreased body weight, delayed maturation, and decreased fertility in adulthood. There was some maternal toxicity at this dose.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
肝毒性
在上市前的研究中，服用维拉唑酮的患者肝功能测试异常并不常见（
In premarketing studies, liver test abnormalities were uncommon in patients taking vilazodone (
◉ Summary of Use during Lactation:Because there is no published experience with vilazodone during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking vilazodone.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.
Concomitant administration of vilazodone and moderate CYP3A4 inhibitors (e.g., erythromycin) can result in increased plasma vilazodone concentrations. During concurrent administration with moderate inhibitors of CYP3A4 (e.g., erythromycin), the dosage of vilazodone should be reduced to 20 mg once daily in patients experiencing intolerable adverse effects.
Concomitant administration of vilazodone and potent CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole) can increase plasma vilazodone concentrations by approximately 50%. The manufacturer states that the dosage of vilazodone should be reduced to 20 mg once daily if administered concomitantly with a potent CYP3A4 inhibitor.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
吸收
维拉佐酮与食物同服时的生物利用度为72%。
Vilazodone's bioavailability is 72% when taken with food.
来源:DrugBank
吸收、分配和排泄
消除途径
剂量的1%在尿液中以未改变的形式回收，剂量的2%在粪便中以未改变的形式回收。
1% of the dose is recovered unchanged in the urine and 2% of the dose is recovered unchanged in the feces.
来源:DrugBank
吸收、分配和排泄
分布容积
维拉佐酮的分布体积未知但很大
Vilazodone's volume of distribution is unknown but large
Vilazodone concentrations peak at a median of 4-5 hours (Tmax) after administration and decline with a terminal half-life of approximately 25 hours. The absolute bioavailability of vilazodone is 72% with food. Administration of VIIBRYD with food (high fat or light meal) increases oral bioavailability (Cmax increased by approximately 147-160%, and AUC increased by approximately 64-85%).
[EN] A PROCESS FOR PREPARATION OF 2-BENZOFURANCARBOXAMIDE, 5-[4-[4-(5CYANO-1H-INDOL-3-YL)BUTYL]-1-PIPERAZINYL] FREE BASE AND ITS HYDROCHLORIDE SALT [FR] PROCÉDÉ DE PRÉPARATION DE LA BASE LIBRE 2-BENZOFURANCARBOXAMIDE, 5-[4-[4-(5-CYANO-1H-INDOL-3-YL)BUTYL]-1-PIPÉRAZINYLE], ET DE SON SEL CHLORHYDRATE
Synthesis and Structure−Activity Relationship in a Class of Indolebutylpiperazines as Dual 5-HT<sub>1A</sub> Receptor Agonists and Serotonin Reuptake Inhibitors
作者：Timo Heinrich、Henning Böttcher、Rolf Gericke、Gerd D. Bartoszyk、Soheila Anzali、Christoph A. Seyfried、Hartmut E. Greiner、Christoph van Amsterdam
DOI：10.1021/jm040793q
日期：2004.9.1
Systematic structural modifications of indolealkylphenylpiperazines led to improved selectivity and affinity within this class of 5-HT(1A) receptor agonists. Introduction of electron-withdrawing groups in position 5 on the indole raises serotonin transporter affinity, and the cyano group proved to be the best substituent here. 5-Fluoro and 5-cyano substituted indoles show comparable results in in vitro
PROCESS FOR THE PREPARATION OF VILAZODONE HYDROCHLORIDE AND ITS AMORPHOUS FORM
申请人：ALEMBIC PHARMACEUTICALS LIMITED
公开号：US20150087835A1
公开（公告）日：2015-03-26
The present invention relates to an improved process for the preparation of vilazodone Hydrochloride and a process for preparation of novel pure amorphous form of vilazodone hydrochloride.
本发明涉及一种改进的维拉唑酮盐酸盐制备工艺，以及一种制备新型纯非晶态维拉唑酮盐酸盐的工艺。
PROCESS FOR PREPARING VILAZODONE HYDROCHLORIDE
申请人：Ferrari Massimo
公开号：US20130225818A1
公开（公告）日：2013-08-29
The present invention relates, in a first aspect, to a process preparing vilazodone hydrochloride that comprises the reaction of 3-(4-chloro-1-hydroxy-butyl)-1H-indol-5-carbonitrile with 5-piperazin-1-yl-benzofuran-2-carboxylate methyl hydrochloride with the formation of a 1,4-piperazine, with subsequent dehydration, hydrogenation and treatment with ammonia, to obtain vilazodone in free base form that is then converted into the hydrochloride thereof.
[EN] PROCESS FOR THE PREPARATION OF VILAZODONE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF<br/>[FR] PROCÉDÉ POUR LA PRÉPARATION DE VILAZODONE OU D'UN SEL PHARMACEUTIQUEMENT ACCEPTABLE DE CELLE-CI
申请人：RANBAXY LAB LTD
公开号：WO2014061000A1
公开（公告）日：2014-04-24
The present invention provides a novel intermediate of vilazodone and its process of preparation. The present invention further provides a process for preparing vilazodone or a pharmaceutically acceptable salt thereof using the novel intermediate.
Chromenonindol-Derivate der Formel (I) worin R1, R2, R3, R, A und B die in Anspruch 1 angegebenen Bedeutungen besitzen, sowie deren pharmazeutisch verwendbaren Prodrugs, Derivate, Solvate, Stereoisomere und Salze zeigen besondere Wirkungen auf das Zentralnervensystem, vor allem 5 HT-Wiederaufnahme hemmende und 5 HTx-agonistische und/oder-antagonistische Wirkungen. Sie zeichnen sich durch eine besonders hohe Bioverfügbarkeit und eine besonders hohe Hemmung der 5 HT-Wiederaufnahme aus.
Chromenonindol-Derivate der Formel (I)，其中R1、R2、R3、R、A和B具有权利要求1中所述的含义，以及它们的药用可用前药、衍生物、溶剂化合物、立体异构体和盐对中枢神经系统表现出特殊作用，尤其是5-HT再摄取抑制和5-HTx激动和/或拮抗作用。它们具有特别高的生物利用度和对5-HT再摄取的特别高抑制作用。
