TABLE 5

Summary and comparison of simulated PK and DDI parameters of E7766 from PBPK models using two scenarios

SimCYP default compound for Rifampicin was used for simulations. For scenario 1, hepatic uptake clearance was assigned from the transporter kinetics measured in HEK293 cells, and for scenario 2, intrinsic active uptake clearance measured in from SCHH was assigned to OATP1B3.

PK Profile Parameters of E7766Scenario 1Scenario 2
(−) Rifampicin(+) Rifampicin(−) Rifampicin(+) Rifampicin
AUCtotal (nmol·h/l)47.38131.0667.26174.07
 AUCtotal ratio2.772.59
Cmax,tot (nmol/l)474.01479.92476.24480.12
Cmax,tot ratio1.011.01
CLtot,p (l/h)29.6211.8821.558.66
 CLtot,p ratio0.400.40
Liver intracellular AUCfree (nmol·h/l)76.1969.0671.3561.28
 Liver intracellular AUCfree ratio0.910.86
  • AUCtotal ratio, ratio of AUCtotal in the presence and absence of the inhibitor; CLtot,p ratio, ratio of CLtot,p in the presence and absence of the inhibitor; Cmax,tot, maximum total plasma conc.; Cmax,tot ratio, ratio of Cmax,tot in the presence and absence of the inhibitor; liver intracellular AUCfree ratio, ratio of area under free intrahepatocellular conc.-time curve in the presence and absence of the inhibitor.