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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor
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Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor

机译：肝损伤对Grazoprevir的药代动力学，丙型肝炎病毒蛋白酶抑制剂的影响

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Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multipledose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steadystate GZR AUC(0-24) (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was approximate to 2-, approximate to 5-, or approximate to 12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.
机译：Grazoprevir（GZR）加尔巴斯维尔是乙型肝炎病毒（HCV）基因型1或4的慢性感染的批准治疗。HCV感染并发症包括肝硬化，终级肝病和肝细胞癌。本研究的目的是评估乘法糖（200,100，或50mg）的非HCV参与者的药代动力学和安全性，分别分别和健康匹配对照（HI）和健康匹配对照（协议MK-5172_P013; Merck＆Co.，Inc。，Kenilworth，NJ）。与种族，年龄，性别和体重指数相匹配的温和，中度或严重HI和对照（年龄18至65岁）的参与者参加了3部分，开放标签，顺序面板的药代动力学研究。参与者在每日10天内接受口服剂量的GZR 200mg（两种100mg片剂），100mg（100mg片剂），或50mg（25毫克片剂）10天。共有50名参与者注册：8例，温和的HI，9，中等HI，8，均为严重HI，以及每种肝脏队列的对应数量的健康匹配对照。嗨的参与者展示了比健康的匹配对照更高的GZR暴露，并随着HA严重程度的增加而导致暴露。对于有轻度，中等或严重HI的参与者的参与者，稳定的GZR AUC（0-24）（从0到24小时的浓度 - 时间曲线下的区域）近似为2-，约为5-，或近似为12倍分别比健康匹配对照的更高。 GZR通常在与您的参与者中耐受良好。在HCV与温和嗨的人们中，GZR不需要剂量调整。 GZR对具有中等或严重HI的人（Child-Pugh Bass B或C）进行禁用，因为它们可能会显着增加GZR暴露，这可能导致转氨酶升高的风险增加。

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