methyl N-[1-[2-[[4-[1-(4-tert-butylphenyl)-5-[4-[[1-[2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]phenyl]pyrrolidin-2-yl]phenyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: methyl N-[1-[2-[[4-[1-(4-tert-butylphenyl)-5-[4-[[1-[2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]phenyl]pyrrolidin-2-yl]phenyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
• 化学式: C₅₀H₆₇N₇O₈
• 分子量: 894.1
• InChiKey: PIDFDZJZLOTZTM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.9
• 重原子数：
  65
• 可旋转键数：
  16
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  179
• 氢给体数：
  4
• 氢受体数：
  9

ADMET

毒理性

• 肝毒性

在大规模随机对照试验中，使用Viekira Pak治疗的患者的血清转氨酶升高超过正常上限（ULN）5倍的发生率为1%至2%，这一比率低于安慰剂治疗（3%至7%）的发生率。这些升高通常是无需调整剂量即可无症状和短暂地解决，大约1%的患者需要停药。尽管在治疗期间血清酶升高频率较高，但在注册前的研究中很少报告有临床明显的肝损伤。然而，自从Viekira Pak在美国普遍使用以及在其它地方多年的临床使用期间，偶尔会有报告出现明显的血清转氨酶升高伴有症状和轻度黄疸的情况，尽管这些情况在已发表的文献中没有描述。此外，一些患有慢性丙型肝炎和晚期肝硬化的患者在D-O-P/r治疗期间突然出现肝功能失代偿。接受其他口服抗病毒组合治疗，如索非布韦与达卡他韦、雷迪帕韦或西美瑞韦治疗的患者也描述了类似的发作。因此，这种现象可能与特定药物无关，而是对所有强效丙型肝炎抗病毒治疗的共同反应，可能是对突然清除HCV的悖论性反应。或者，这些发作可能是自发的、巧合的，与抗病毒治疗无关。这些治疗在肝硬化患者中的试验没有安慰剂对照，因此无法很好地定义肝硬化患者因丙型肝炎而自发肝功能失代偿的比率。无论原因如何，高达10%的肝硬化患者在强效抗病毒治疗期间出现肝功能失代偿的情况，使得前瞻性监测是可取的，如果出现肝功能衰竭的证据，应立即停止治疗。 因此，Viekira Pak方案中包含的五种抗病毒化合物（达沙布韦、奥比他韦、帕里他韦、利托那韦和利巴韦林）与治疗期间突然ALT升高的情况有关，但很少与临床上明显的肝损伤有关。在已有肝硬化的患者中，使用Viekira Pak进行抗病毒治疗与乳酸酸中毒和肝功能失代偿的发作有关。这些突然、严重的不良事件的原因尚不清楚，但它们通常是严重且威胁生命的，需要立即停止治疗，进行重症监护管理，并考虑紧急肝移植。 可能性评分：C（可能在已有肝硬化的患者中引起肝损伤的原因）。

In large randomized controlled trials, serum aminotransferase elevations more than 5 times the upper limit of normal (ULN) occurred in 1% to 2% of Viekira Pak treated patients. Interestingly, this rate was lower than occurred with placebo therapy (3% to 7%). The elevations were generally asymptomatic and short lived, resolving with or without dose modification and requiring drug discontinuation in approximately 1% of patients. Despite the frequency of serum enzyme elevations during therapy, clinically apparent liver injury was rarely reported in preregistration studies. However, since the general availability of Viekira Pak in the United States and during years of clinical use elsewhere, occasional instances of marked serum aminotransferase elevations with symptoms and mild jaundice have been reported, although not described in the published literature. Furthermore, some patients with chronic hepatitis C and advanced cirrhosis have developed sudden hepatic decompensation during therapy with D-O-P/r. Similar episodes have been described in patients receiving other oral antiviral combinations such as sofosbuvir with daclatasvir, ledipasvir or simeprevir. Thus, this phenomenon may be unrelated to a specific agent, but rather common to all potent antiviral therapies for hepatitis C and perhaps is a paradoxical response to sudden clearance of HCV. Alternatively, these episodes may be spontaneous, coincidental and unrelated to the antiviral therapy. Trials of these therapies in patients with cirrhosis have not been placebo controlled so that the rate of spontaneous hepatic decompensation in patients with cirrhosis due to hepatitis C is not well defined. Whatever the reason, the occurrence of decompensation in up to 10% of patients with cirrhosis undergoing potent antiviral therapy makes prospective monitoring advisable and prompt discontinuation of treatment if evidence of hepatic failure supervenes. Thus, the five antiviral compounds included in Viekira Pak regimens (dasabuvir, ombitasvir, paritaprevir, ritonavir and ribavirin) have been linked to instances of sudden ALT elevations during therapy, but uncommonly to clinically apparent liver injury. In patients with preexisting cirrhosis, antiviral therapy with Viekira Pak has been linked to episodes of lactic acidosis and hepatic decompensation. The cause of these sudden, severe adverse events is unknown but they are usually severe and life threatening, requiring prompt discontinuation of treatment, intensive care management and consideration of emergency liver transplantation. Likelihood score: C (probable cause of liver injury arising in patients with pre-existing cirrhosis).

来源:LiverTox