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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  in vitro  study using OATP1B1-MRP2 expressing cells. [ 14 C]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  in vitro  study using OATP1B1-MRP2 expressing cells. [ 14 C]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.

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