近日，Jynarque（tolvaptan，托伐普坦）获美国FDA批准上市，用于存在病情快速进展风险的常染色体显性多囊肾病（ADPKD）成人患者，以延缓肾功能的下降。
tolvaptan是一种血管加压素V2受体拮抗剂，每日口服2次，该药具有一种独特的作用机制，仅仅促进水的排泄而不会影响其他电解质如钠离子的排泄。血管加压素是一种激素，正常情况下通过刺激肾脏的水重吸收来维持机体水分平衡。在ADPKD患者中，血管加压素水平高于正常人群。高水平的血管加压素能促进囊肿的生长，从而使肾脏肿胀体积增大。tolvaptan通过阻断血管加压素的作用，减缓肾囊肿的生长速度。
批准日期：2018年4月27日 公司：日本大冢制药
JYNARQUETM(托伐普坦[tolvaptan])片,为口服使用
美国初次批准: 2009
作用机制
Tolvaptan是一种选择性血管加压素V2-受体拮抗剂有一个对V2-受体亲和力3为1.8倍天然精氨酸血管加压素(AVP)。Tolvaptan对V2-受体亲和力是29倍对V1a-受体。血管加压素对V2-受体在肾中减低的结合较低腺苷酸环化酶活性导致一个减低在细胞内腺苷 3′，5′-环单磷酸(cAMP)浓度。减低的cAMP浓度阻止水通道蛋白[aquaporin] 2含囊泡从与浆膜融合，它转而致一个增加在尿中水排泄，一个增加在游离水清除率(aquaresis)和一个减低在尿中渗透压。在人ADPKD[常染色体显性多囊肾病]囊表皮细胞，tolvaptan抑制AVP-刺激的在体外囊生长和氯化物-依赖液体分泌至囊泡。在动物模型中，减低的cAMP浓度被伴随减低在总肾容积的生长率和肾囊泡的形成率和扩大。Tolvaptan代谢物与tolvaptan比较无或弱拮抗剂活性对人V2-受体。
适应证和用途
JYNARQUE是一种选择性血管加压素V2-受体拮抗剂适用于减慢肾功能下降在成年处于迅速地进展性常染色体显性多囊肾病[常染色体显性多囊肾病(ADPKD[常染色体显性多囊肾病])]的风险。
剂量和给药方法
推荐剂量
对JYNARQUE的初始剂量是60mg口服每天作为45mg在醒来时服用和15mg服用8小时以后。滴定调整至60mg加30mg然后至90 mg加30 mg每天如耐受滴定有间至少每周间隔。患者可能向下-滴定根据耐受性。鼓励患者饮足够水避免口渴或脱水。
监视
期缓和显著或不可逆肝脏损伤的风险，JYNARQUE的开始前，在开始后咋2和周，每月共18个月和其后每3个月进行对 ALT，AST和胆红素血测试。监视对同时症状可能指示肝损伤[见警告和注意事项]。
缺失剂量
如在给药时间表一剂JYNARQUE没有服用，在它的时间表服用下一次剂量。
与CYP 3A抑制剂共同给药
CYP 3A抑制剂
强 CYP 3A抑制剂的同时使用被禁忌[见禁忌证和警告和注意事项]。
在患者正在服用同时中度CYP3A抑制剂，按表1减低JYNARQUE的剂量。考虑进一步减低如患者不能耐受减低的剂量[见警告和注意事项和药物相互作用]。
暂时地中断JYNARQUE对短期用中度CYP 3A抑制剂治疗如推荐的减低剂量不能得到.

剂型和规格
JYNARQUE (tolvaptan)是以非-计分的，蓝色，浅凸出，立即释放片，凹陷有“OTSUKA” 和片强度(mg)在一侧供应。JYNARQUE 15mg片是三角形，30mg片为圆形，45mg 片是方形，60mg片是长方形，和90 mg片是五角形。
禁忌证
JYNARQUE在以下患者中被禁忌:
●显著肝受损或损伤的体征或症状病史，不包括无并发的多囊性肝疾病
●强CYP 3A抑制剂是被禁忌。
● 未校正的异常血钠浓度。
● 对口渴不敏感或反应。
● 低血容积
● 对tolvaptan或任何它的组分超敏性。
● 未校正是尿流出阻塞.
● 无尿
警告和注意事项
● 高钠血症，脱水和低血容积: 可能需要干预.
不良反应
用JYNARQUE最常观察到不良反应(发生率>10%和至少2次对安慰剂)为口渴，多尿，夜尿，烦渴和烦渴.
药物相互作用
避免与以下使用:
● 强CYP 3A诱导剂
● OATP1B1/3和OAT3转运蛋白底物
● BCRP转运蛋白底物
● V2-受体拮抗剂
在特殊人群中使用
● 妊娠: 可能致胎儿危害
● 哺乳: 推荐不哺乳喂养
见17对患者咨询资料和用药指南.
包装供应/贮藏和处置
供应
JYNARQUE(tolvaptan)是被供应如非计分，蓝色，浅凸出，立即释放片，凹陷有“OTSUKA”和片强度(mg)在一侧上。
JYNARQUE(tolvaptan)15mg片是三角形，30mg片为圆形，45mg片为方块，60mg片为长方形，和90mg片为五角形。
JYNARQUE(tolvaptan)片被供应如下:

贮存在20°C至25°C (68°F至77°F)，外出允许15°C和30°C间(59°F至86°F) [见USP 控制室温].

JYNARQUETM (tolvaptan)
INDICATION and IMPORTANT SAFETY INFORMATION for JYNARQUETM (tolvaptan)
INDICATION:
JYNARQUE is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).
IMPORTANT SAFETY INFORMATION:
WARNING: RISK OF SERIOUS LIVER INJURY
•JYNARQUE (tolvaptan) can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported
•Measure transaminases (ALT, AST) and bilirubin before initiating treatment, at 2 weeks and 4 weeks after initiation, then monthly for the first 18 months and every 3 months thereafter. Prompt action in response to laboratory abnormalities, signs, or symptoms indicative of hepatic injury can mitigate, but not eliminate, the risk of serious hepatotoxicity.
•Because of the risks of serious liver injury, JYNARQUE is available only through a Risk Evaluation and Mitigation Strategy program called the JYNARQUE REMS Program
CONTRAINDICATIONS:
•History, signs or symptoms of significant liver impairment or injury. This contraindication does not apply to uncomplicated polycystic liver disease
•Taking strong CYP3A inhibitors
•With uncorrected abnormal blood sodium concentrations
•Unable to sense or respond to thirst
•Hypovolemia
•Hypersensitivity (e.g., anaphylaxis, rash) to JYNARQUE or any component of the product
•Uncorrected urinary outflow obstruction
•Anuria
Serious Liver Injury: JYNARQUE can cause serious and potentially fatal liver injury. Acute liver failure requiring liver transplantation has been reported in the post-marketing ADPKD experience. Discontinuation in response to laboratory abnormalities or signs or symptoms of liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, icterus, dark urine or jaundice) can reduce the risk of severe hepatotoxicity. To reduce the risk of significant or irreversible liver injury, assess ALT, AST and bilirubin prior to initiating JYNARQUE, at 2 weeks and 4 weeks after initiation, then monthly for 18 months and every 3 months thereafter.
Hypernatremia, Dehydration and Hypovolemia: JYNARQUE therapy increases free water clearance which can lead to dehydration, hypovolemia and hypernatremia. Instruct patients to drink water when thirsty, and throughout the day and night if awake. Monitor for weight loss, tachycardia and hypotension because they may signal dehydration. Ensure abnormalities in sodium concentrations are corrected before initiating therapy. If serum sodium increases above normal or the patient becomes hypovolemic or dehydrated and fluid intake cannot be increased, suspend JYNARQUE until serum sodium, hydration status and volume status parameters are within the normal range.
Inhibitors of CYP3A: Concomitant use of JYNARQUE with drugs that are moderate or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, indinavir/ritonavir, ritonavir, and conivaptan) increases tolvaptan exposure. Use with strong CYP3A inhibitors is contraindicated; dose reduction of JYNARQUE is recommended for patients taking moderate CYP3A inhibitors. Patients should avoid grapefruit juice beverages while taking JYNARQUE.
Adverse Reactions: Most common observed adverse reactions with JYNARQUE (incidence >10% and at least twice that for placebo) were thirst, polyuria, nocturia, pollakiuria and polydipsia.
Other Drug Interactions:
•Strong CYP3A Inducers: Co-administration with strong CYP3A inducers reduces exposure to JYNARQUE. Avoid concomitant use of JYNARQUE with strong CYP3A inducers
•OATP1B1/3 and OAT3 Transporter Substrates: Caution should be used in patients who take JYNARQUE and OATP1B1/B3 and OAT3 substrates (e.g., statins, bosentan, glyburide, nateglinide, repaglinide, methotrexate, furosemide), as the plasma concentrations of these substrates may be increased.
•BCRP Transporter Substrates: Tolvaptan is an inhibitor of BCRP. Patients who take JYNARQUE, should avoid concomitant use with BCRP substrates (e.g., rosuvastatin)
•V2-Receptor Agonist: Tolvaptan interferes with the V2-agonist activity of desmopressin (dDAVP). Avoid concomitant use of JYNARQUE with a V2-agonist.
Pregnancy and Lactation: Based on animal data, JYNARQUE may cause fetal harm. In general, JYNARQUE should be discontinued during pregnancy. Advise women not to breastfeed during treatment with JYNARQUE.