Evaluation of the non-linearity of NA808 in liver not reflected in plasma using a rat pharmacokinetic study and PBPK modelling

When NA808, a potent HCV replication inhibitor, was intravenously administered to rats, it was distributed to the liver. The AUC ratio in the liver of 20 mg/kg to 2 mg/kg was greater than the dose ratio, whereas exposure in plasma was increased in a dose-proportional manner. Saturation of biliary excretion was also shown at 20 mg/kg.NA808 was revealed to be a substrate for both OATP1B and MRP2 transporters by an <i>in vitro</i> study using OATP1B1-MRP2 expressing cells. [¹⁴C]NA808 was taken up into the cells by OATP1B1 and excreted from cells by MRP2 efficiently (P_app ratio: 24.2–70.2). The P_app ratio decreased with increasing NA808 concentration.PBPK modelling was constructed to display the blood and liver concentration time profile and biliary excretion of NA808. This model analysis was able to reproduce the pharmacokinetics in rats; the degree of increase in the liver exposure from 2 to 20 mg/kg was more than dose-proportional and was greater than the increase in the blood exposure due to saturation of efflux transporters.In drug development, to avoid unexpected toxicity in tissues, it is important to consider the potential for tissue non-linearity with linear plasma exposure based on pre-clinical data and PBPK modelling. When NA808, a potent HCV replication inhibitor, was intravenously administered to rats, it was distributed to the liver. The AUC ratio in the liver of 20 mg/kg to 2 mg/kg was greater than the dose ratio, whereas exposure in plasma was increased in a dose-proportional manner. Saturation of biliary excretion was also shown at 20 mg/kg. NA808 was revealed to be a substrate for both OATP1B and MRP2 transporters by an <i>in vitro</i> study using OATP1B1-MRP2 expressing cells. [¹⁴C]NA808 was taken up into the cells by OATP1B1 and excreted from cells by MRP2 efficiently (P_app ratio: 24.2–70.2). The P_app ratio decreased with increasing NA808 concentration. PBPK modelling was constructed to display the blood and liver concentration time profile and biliary excretion of NA808. This model analysis was able to reproduce the pharmacokinetics in rats; the degree of increase in the liver exposure from 2 to 20 mg/kg was more than dose-proportional and was greater than the increase in the blood exposure due to saturation of efflux transporters. In drug development, to avoid unexpected toxicity in tissues, it is important to consider the potential for tissue non-linearity with linear plasma exposure based on pre-clinical data and PBPK modelling.

强效丙型肝炎病毒（HCV）复制抑制剂NA808经静脉给药于大鼠后，可分布至肝脏。20 mg/kg与2 mg/kg剂量组的肝脏药时曲线下面积（AUC）比值高于剂量比值，而血浆药物暴露量呈剂量依赖性增加。20 mg/kg剂量下还观察到胆汁排泄饱和现象。通过使用转染OATP1B1-MRP2的细胞开展的体外（in vitro）研究证实，NA808是有机阴离子转运多肽1B（OATP1B）与多药耐药相关蛋白2（MRP2）转运体的底物。[¹⁴C]NA808可被OATP1B1高效摄取进入细胞，并经MRP2从细胞中排出（表观渗透系数（Papp）比值：24.2~70.2）。Papp比值随NA808浓度升高而降低。研究人员构建了生理药代动力学（PBPK）模型，以表征NA808的血液与肝脏浓度-时间曲线及胆汁排泄特征。该模型分析可复现大鼠体内的药代动力学特征：2 mg/kg升至20 mg/kg剂量时，肝脏暴露量的增幅高于剂量增幅，且高于因外排转运体饱和导致的血液暴露量增幅。在药物开发过程中，基于临床前数据与PBPK模型，考量血浆暴露呈线性但组织暴露存在非线性的可能性，对于避免组织中出现意外毒性至关重要。当强效丙型肝炎病毒（HCV）复制抑制剂NA808经静脉给药于大鼠后，其可分布至肝脏。20 mg/kg与2 mg/kg剂量组的肝脏AUC比值高于剂量比值，而血浆药物暴露量呈剂量依赖性增加。20 mg/kg剂量下同样观察到胆汁排泄饱和现象。通过使用转染OATP1B1-MRP2的细胞开展的体外（in vitro）研究证实，NA808是OATP1B与MRP2转运体的底物。[¹⁴C]NA808可被OATP1B1高效摄取进入细胞，并经MRP2从细胞中排出（Papp比值：24.2~70.2）。Papp比值随NA808浓度升高而降低。研究人员构建了PBPK模型，以表征NA808的血液与肝脏浓度-时间曲线及胆汁排泄特征。该模型分析可复现大鼠体内的药代动力学特征：2 mg/kg升至20 mg/kg剂量时，肝脏暴露量的增幅高于剂量增幅，且高于因外排转运体饱和导致的血液暴露量增幅。在药物开发过程中，基于临床前数据与PBPK模型，考量血浆暴露呈线性但组织暴露存在非线性的可能性，对于避免组织中出现意外毒性至关重要。