VX-950(Telaprevir)

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: VX-950(Telaprevir)
• 英文别名: 2-[2-[[2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide
• 化学式: C₃₆H₅₃N₇O₆
• 分子量: 679.8
• InChiKey: BBAWEDCPNXPBQM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  49
• 可旋转键数：
  14
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  180
• 氢给体数：
  4
• 氢受体数：
  8

ADMET

代谢

特拉匹韦在肝脏中被广泛代谢，涉及水解、氧化和还原。在粪便、血浆和尿液中检测到多种代谢物。在反复口服给药后，特拉匹韦的R-对映体（活性降低30倍）、吡嗪酸和一种在特拉匹韦的α-酮酰胺键发生还原的代谢物（无活性）被确定为特拉匹韦的主要代谢物。

Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in feces, plasma, and urine. After repeated oral administration, the R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the alpha-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

特拉匹韦是CYP3A的强抑制剂。特拉匹韦与那些高度依赖CYP3A清除且血药浓度升高与严重和/或生命威胁性事件（治疗指数狭窄）相关的药物联合使用是禁忌的。特拉匹韦与强烈诱导CYP3A的药物联合使用也是禁忌的，因为这可能导致特拉匹韦的暴露量降低和疗效丧失。

Telaprevir is a strong inhibitor of CYP3A. Telaprevir is contraindicated when combined with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Telaprevir is contraindicated when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of telaprevir.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

Potential pharmacokinetic interaction with drugs that are inducers or inhibitors of P-glycoprotein, with possible alteration in telaprevir concentrations. 可能与其他药物产生药代动力学相互作用，这些药物是P-糖蛋白的诱导剂或抑制剂，可能会改变泰拉普雷韦的浓度。

Potential pharmacokinetic interaction with drugs that are inducers or inhibitors of P-glycoprotein, with possible alteration in telaprevir concentrations.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与alfuzosin（增加alfuzosin浓度）可能存在药代动力学相互作用。因为增加的alfuzosin浓度可能导致低血压或心脏心律不齐，所以禁忌同时使用telaprevir和alfuzosin。

Potential pharmacokinetic interaction with alfuzosin (increased alfuzosin concentrations). Concomitant use of telaprevir and alfuzosin is contraindicated because increased alfuzosin concentrations may result in hypotension or cardiac arrhythmia.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与抗心律失常药物（如胺碘酮、苄普地尔（在美国已不再商业销售）、氟卡尼、系统性利多卡因、普罗帕酮、奎尼丁）可能存在潜在的药代动力学相互作用，可能导致抗心律失常药物的浓度增加；存在严重和/或危及生命的不良反应风险。如果同时使用特拉普韦和抗心律失常药物，应谨慎并加强临床监测。

Potential pharmacokinetic interaction with antiarrhythmic agents (amiodarone, bepridil (no longer commercially available in US), flecainide, systemic lidocaine, propafenone, quinidine) may result in increased concentrations of the antiarrhythmic agent; potential for serious and/or life-threatening adverse effects. If telaprevir and antiarrhythmic agents are used concomitantly, use caution and clinical monitoring.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

对于特拉普雷韦过量，没有特定的解毒剂。特拉普雷韦过量的治疗包括一般的支持性措施，包括监测生命体征和观察患者的临床状态。在发生过量时，采取标准的支持性措施是合理的，例如，从胃肠道中清除未吸收的物质，进行临床监测（包括获取心电图），并在需要时建立支持性治疗。目前尚不清楚特拉普雷韦是否可以通过腹膜透析或血液透析清除。

No specific antidote is available for overdose with telaprevir. Treatment of overdose with telaprevir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. In the event of an overdose, it is reasonable to employ the standard supportive measures, such as, removing unabsorbed material from the gastrointestinal tract, employing clinical monitoring (including obtaining an electrocardiogram), and instituting supportive therapy if required. It is not known whether telaprevir is dialyzable by peritoneal or hemodialysis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

特拉普雷韦的药代动力学特性已经在健康成年受试者和慢性丙型肝炎受试者中进行了评估。在未经治疗的1型慢性丙型肝炎患者中，特拉普雷韦（750毫克，每8小时一次）与聚乙二醇干扰素α和利巴韦林联合使用多次给药后，平均（标准差）Cmax为3510（1280）ng/mL，Cmin为2030（930）ng/mL，AUC8h为22,300（8650）ng·小时/mL。

The pharmacokinetic properties of telaprevir have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following multiple doses of telaprevir (750 mg every 8 hr) in combination with peginterferon alfa and ribavirin in treatment-naive subjects with genotype 1 chronic hepatitis C, mean (SD) Cmax was 3510 (1280) ng/mL, Cmin was 2030 (930) ng/mL, and AUC8h was 22,300 (8650) ng.hr/mL.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

特拉匹韦口服给药，最可能在小肠吸收，没有证据表明在大肠吸收。单次给药后，特拉匹韦的最大血浆浓度通常在4到5小时内达到。

Telaprevir is orally available, most likely absorbed in the small intestine, with no evidence for absorption in the colon. Maximum plasma concentrations after a single dose of telaprevir are generally achieved after 4 to 5 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

特拉匹韦是P-糖蛋白运输的底物和抑制剂。

Telaprevir is a substrate for and inhibitor of P-glycoprotein transport.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

当与标准高脂餐（含533千卡和21克脂肪）一起服用时，泰拉普雷韦的全身暴露量（AUC）比空腹条件下服用时增加了237%。此外，餐食的类型显著影响对泰拉普雷韦的暴露。与空腹相比，当与低脂餐（249千卡，3.6克脂肪）和高脂餐（928千卡，56克脂肪）一起服用泰拉普雷韦时，泰拉普雷韦的全身暴露量（AUC）分别增加了大约117%和330%。

The systemic exposure (AUC) to telaprevir was increased by 237% when telaprevir was administered with a standard fat meal (containing 533 kcal and 21 g fat) compared to when telaprevir was administered under fasting conditions. In addition, the type of meal significantly affects exposure to telaprevir. Relative to fasting, when telaprevir was administered with a low-fat meal (249 kcal, 3.6 g fat) and a high-fat meal (928 kcal, 56 g fat), the systemic exposure (AUC) to telaprevir was increased by approximately 117% and 330%, respectively.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• pH sensitive matrix formulation
  申请人：Schering Corporation

  公开号：EP2428204A2

  公开（公告）日：2012-03-14

  The present invention provides formulations of therapeutic agents that benefit from a prolonged time of controlled release in the stomach and upper gastrointestinal (GI) tract, and from an enhanced drug exposure to the upper GI tract. The formulations of the invention comprise a therapeutic agent and one or more pH sensitive polymers that are designed for accelerated hydration, expansion, disintegration and dissolution at the higher pH of the upper GI tract, thereby, ensuring that any therapeutic agent that has not been released in the stomach is released in the upper GI tract, thus maximizing absorption of therapeutic agent that has a window of absorption located at the upper GI tract.

  本发明提供的治疗剂制剂可延长在胃和上消化道（GI）中的控释时间，并增强药物在上消化道中的暴露。本发明的制剂由治疗剂和一种或多种 pH 值敏感聚合物组成，这些聚合物的设计目的是在上消化道较高的 pH 值下加速水化、膨胀、崩解和溶解，从而确保任何未在胃中释放的治疗剂在上消化道中释放，从而最大限度地提高上消化道吸收窗口的治疗剂的吸收率。
• Medicaments and methods combining a HCV protease inhibitor and an AKR competitor
  申请人：Ghosal Anima

  公开号：US20070207949A1

  公开（公告）日：2007-09-06

  Disclosed are medicaments, pharmaceutical compositions, pharmaceutical kits, and methods based on combinations of a hepatitis C virus (HCV) protease inhibitor and an aldo-keto reductase (AKR) competitor, for concurrent or consecutive administration in treating, preventing, or ameliorating one or more symptoms of HCV, treating disorders associated with HCV, or inhibiting cathepsin activity in a subject.
• Controlled-release formulation of HCV protease inhibitor and methods using the same
  申请人：Malcolm A. Bruce

  公开号：US20070237818A1

  公开（公告）日：2007-10-11

  Controlled-release dosage formulations including at least one compound of Formulae I to XXVIII herein and a controlled-release carrier and methods of treatment using the same are provided.
• Process for the precipitation and isolation of 6,6-Dimethyl-3-Aza Bicyclo [3.1.0] Hexane-Amide compounds by controlled precipitation and pharmaceutical formulations containing same
  申请人：Zarkadas Dimitrios

  公开号：US20080193518A1

  公开（公告）日：2008-08-14

  The present invention provides a method of continuous precipitation and isolation of an amorphous solid particulate form of 3-[2-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-6,6-dimethyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid (2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide having controlled physical properties. The present invention provides also pharmaceutical formulations comprising the precipitated compound.
• Process for the precipitation and isolation of 6,6-dimethyl-3-aza-bicyclo [3.1.0] hexane-amide compounds by controlled precipitation and pharmaceutical formulations containing same
  申请人：Zarkadas Dimitrios

  公开号：US20080254128A1

  公开（公告）日：2008-10-16

  The present invention provides a method of continuous precipitation and isolation of an amorphous solid particulate form of 3-[2-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-6,6-dimethyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid (2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide having controlled physical properties. The present invention provides also pharmaceutical formulations comprising the precipitated compound.