Wright D Hamish, Caro Luzelena, Cerra Michael, Panorchan Paul, Du Lihong, Anderson Melanie, Potthoff Andrej, Nachbar Robert B, Wagner John, Manns Michael P, Talal Andrew H
Merck and Company, Whitehouse Station, NJ, USA.
Antivir Ther. 2015;20(8):843-8. doi: 10.3851/IMP2958. Epub 2015 Apr 7.
Some drugs that are actively taken up into the liver exhibit greater than dose proportional increases in plasma exposure, although human liver-to-plasma concentration ratios have rarely been evaluated. Understanding these relationships has implications for drug concentrations at the target site for certain classes of compounds, such as direct-acting antivirals, targeted towards HCV.
Treatment-experienced, chronic HCV non-cirrhotic patients (n=3) received vaniprevir (600 mg or 300 mg twice daily) on days 1-3 and (600 mg or 300 mg single dose) on day 4. Core needle biopsy was performed at 6 or 12 h post-dose on day 4. Blood samples were collected pre-dose on days 1 and 4, and for 24 h post-dose on day 4. The primary study objective was the hepatic concentration of vaniprevir at 6 and 12 h post-dose.
Vaniprevir plasma pharmacokinetic parameters increased in a greater than dose-proportional manner between the 300 mg and 600 mg doses, with approximately fivefold increases in AUC0-12 and Cmax associated with a twofold increase in dose (AUC0-12, 10.6 μM/h to 59.5 μM/h; Cmax, 2.60 μM to 13.5 μM). In the 300 mg and 600 mg dose groups, mean liver concentrations of vaniprevir were 84.6 μM and 169 μM at 6 h post-dose, and 29.4 μM and 53.7 μM at 12 h post-dose. Liver concentrations were higher than plasma with liver-to-plasma concentration ratios of approximately 20-280.
These data confirm higher vaniprevir concentrations in human liver compared with plasma and demonstrate that measurement of human liver drug concentration using needle biopsy is feasible.
一些被肝脏主动摄取的药物在血浆暴露量上呈现出大于剂量比例的增加，尽管人类肝脏与血浆浓度比很少被评估。了解这些关系对于某些类别的化合物（如针对丙型肝炎病毒的直接作用抗病毒药物）在靶部位的药物浓度具有重要意义。
有治疗经验的慢性丙型肝炎非肝硬化患者（n = 3）在第1 - 3天接受万尼普韦（600 mg或300 mg，每日两次），并在第4天接受（600 mg或300 mg单剂量）。在第4天给药后6或12小时进行核心针吸活检。在第1天和第4天给药前采集血样，并在第4天给药后24小时内采集血样。主要研究目标是给药后6小时和12小时万尼普韦的肝脏浓度。
万尼普韦血浆药代动力学参数在300 mg和600 mg剂量之间以大于剂量比例的方式增加，AUC0 - 12和Cmax增加约五倍，而剂量增加两倍（AUC0 - 12，从10.6 μM/h增加到59.5 μM/h；Cmax，从2.60 μM增加到13.5 μM）。在300 mg和600 mg剂量组中，给药后6小时万尼普韦的平均肝脏浓度分别为84.6 μM和169 μM，给药后12小时分别为29.4 μM和53.7 μM。肝脏浓度高于血浆，肝脏与血浆浓度比约为20 - 280。
这些数据证实了人类肝脏中万尼普韦的浓度高于血浆，并表明使用针吸活检测量人类肝脏药物浓度是可行的。
