Grazoprevir is partially eliminated by oxidative metabolism meditated by CYP3A [FDA Label]. No circulating metabolites of have been detected in human plasma.
In large randomized controlled trials, serum aminotransferase elevations more than 5 times the upper limit of normal (ULN) occurred in 1% of Zepatier treated patients, but were infrequent in placebo recipients. The elevations were generally asymptomatic and short-lived, often arising after the first 4 weeks of therapy and resolving with or without dose modification and only rarely requiring early discontinuation. In some instances, ALT levels rose above 10 times the upper limit of normal, but these elevations were not accompanied by symptoms or jaundice and were invariably self-limited. In the many preregistration trials, Zepatier was not associated with instances of clinically apparent liver injury.
However, two forms of liver injury have been associated with direct-acting antiviral agents used to treat chronic hepatitis C, and these reactions appear to occur with all regimens. The first is acute decompensation of HCV-related cirrhosis. The liver injury usually arises within 2 to 6 weeks of starting antiviral therapy, but can occur later and even after discontinuation. The injury is marked by worsening jaundice and appearance of signs of hepatic failure such as ascites or hepatic encephalopathy, often with little or no change in serum aminotransferase levels. Lactic acidosis may be present early. The course is variable but calls for prompt discontinuation of treatment despite successful suppression of HCV RNA levels. Some instances have led to death or need for emergency liver transplantation. For this reason, patients with cirrhosis undergoing antiviral therapy with potent direct acting agents, such as Zepatier, should be monitored carefully, particularly during the first few weeks of treatment. This syndrome has not been clearly linked to therapy with grazoprevir and elbasvir, but this regimen has not been evaluated in patients with advanced cirrhosis due to hepatitis C.
A second, liver complication of therapy of chronic hepatitis C is reactivation of hepatitis B. This occurs most frequently in patients who have HBsAg in serum but rare instances have arisen in subjects with anti-HBc without HBsAg. The cause of the reactivation of hepatitis B during antiviral therapy of hepatitis C is unknown, but may relate to the inhibition of HBV replication during HCV replication. For this reason, patients with hepatitis C who are to receive antiviral therapy should be screened for HBsAg and anti-HBc. Those with HBsAg are best managed by concurrent treatment with an antiviral agent active against HBV, such as entecavir or tenofovir. Subjects with anti-HBc without HBsAg rarely experience reactivation and can be managed by careful monitoring for HBV DNA levels during treatment and institution of therapy for HBV if levels appear de novo or rise significantly. Reactivation of hepatitis B has been described with many regimens, although not specifically with grazoprevir and elbasvir.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
来源:LiverTox
毒理性
毒性总结
所有强度中最常见的不良反应（在安慰剂对照试验中大于或等于5%）是疲劳、头痛和恶心【FDA标签】。
The most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache, and nausea [FDA Label].
Grazoprevir reaches peak plasma concentration 0.5-3 hours after administration [FDA Label]. Grazoprevir has an absolute bioavailability of 27%. When taken with food the peak concentration of Grazoprevir increases 2.8 fold but this increase in exposure has not been deemed clinically relevant.
Grazoprevir has an estimated apparent volume of distribution of 1250 liters [FDA Label]. It is thought to distribute primarily to the liver with its uptake facilitated by organic anion transporting polypeptide 1B1/3.
来源:DrugBank
吸收、分配和排泄
清除
grazoprevir的清除率尚未确定。
The clearance of Grazoprevir has not been determined [FDA Label].
