TABLE 1

Downregulation and fraction unbound parameters applied in PBPK simulations

CYP1A2CYP3A4
EC50 (nM) (total NN1177 conc. in hepatocyte incubation approximated to fit observed mRNA dataa)4040
Scenario 1: EC50 (nM unbound NN117b), in vitro fu assumed 0.00230.0920.092
Scenario 2: EC50 (nM unbound NN117b) in vitro fu assumed 0.0642.582.58
Scenario 3: EC50 (nM unbound NN117b) in vitro fu assumed 0.010.400.40
Emax0.600.85
  • conc., concentration.

  • aValues are approximated based on 3 concentrations. Based on this uncertainty, the results should be interpreted with caution.

  • bEC50 values for unbound NN1177 for the different scenarios of in vitro fu were calculated as EC50 for the total NN1177 multiplied by the in vitro fu.