Guan Xiao-Duo, Tang Xian-Ge, Zhang Ying-Jun, Xie Hong-Ming, Luo Lin, Wu Dan, Chen Rui, Hu Pei
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Beijing, China.
Front Pharmacol. 2021 Jan 28;11:617122. doi: 10.3389/fphar.2020.617122. eCollection 2020.
Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural protein 5A inhibitor for the treatment of chronic HCV genotype 1 infection. The objective of this analysis was to develop a population pharmacokinetic model of yimitasvir in Chinese healthy volunteers and HCV infection patients. The model was performed using data from 219 subjects across six studies. Nonlinear mixed effects models were developed using Phoenix NLME software. The covariates were evaluated using a stepwise forward inclusion ( < 0.01) and then a backward exclusion procedure ( < 0.001). A two-compartment model with sequential zero-first order absorption and first-order elimination reasonably described yimitasvir pharmacokinetics (PK). The apparent oral clearance and central volume of distribution were 13.8 l·h and 188 l, respectively. The bioavailability (F) of yimitasvir decreased 12.9% for each 100 mg dose increase. Food was found to affect absorption rate (Ka) and F. High-fat meal decreased Ka and F by 90.9% and 38.5%, respectively. Gender and alanine aminotransferase were identified as significant covariates on apparent oral clearance. Female subjects had lower clearance than male subjects. Zero-order absorption duration was longer in healthy volunteers (2.17 h) than that in patients (1.43 h). The population pharmacokinetic model described yimitasvir PK profile well. Food decreased Ka and F significantly, so it was recommended to take yimitasvir at least 2 h before or after a meal. Other significant covariates were not clinically important.
依米他韦是一种新型口服丙型肝炎病毒（HCV）非结构蛋白5A抑制剂，用于治疗慢性HCV 1型感染。本分析的目的是建立依米他韦在中国健康志愿者和HCV感染患者中的群体药代动力学模型。该模型使用来自六项研究的219名受试者的数据进行构建。使用Phoenix NLME软件建立非线性混合效应模型。使用逐步向前纳入法（<0.01）评估协变量，然后使用向后排除法（<0.001）进行评估。具有序贯零级-一级吸收和一级消除的二室模型合理地描述了依米他韦的药代动力学（PK）。表观口服清除率和中央分布容积分别为13.8 l·h和188 l。依米他韦的生物利用度（F）每增加100 mg剂量下降12.9%。发现食物会影响吸收速率（Ka）和F。高脂餐分别使Ka和F降低90.9%和38.5%。性别和丙氨酸氨基转移酶被确定为表观口服清除率的显著协变量。女性受试者的清除率低于男性受试者。健康志愿者的零级吸收持续时间（2.17 h）比患者（1.43 h）更长。群体药代动力学模型很好地描述了依米他韦的PK特征。食物显著降低了Ka和F，因此建议在饭前或饭后至少2小时服用依米他韦。其他显著协变量在临床上并不重要。
