TABLE 1

Prediction from hepatocytes [hepatic clearance (CLH) and availability (FH)] and observed pharmacokinetics in preclinical species [total body (plasma) clearance (CLtot,obs), oral bioavailability (FPO), and absorption fraction × intestinal availability (fa⋅FG)]

Data represent mean ± S.D. (n = 3).

DrugSpeciesCLint,in vitroaPredicted CLHbPredicted FHcCLtot,obsdFPOefa⋅FGf
µl/min/106 cellsml/min/kgml/min/kg
AfatinibRat0.71 ± 0.032.3 ± 0.10.99 ± 0.0090 ± 100.38 ± 0.160.39 ± 0.16
Dog1.7 ± 0.27.6 ± 0.60.96 ± 0.0064 ± 30.81 ± 0.010.85 ± 0.01
Monkey1.1 ± 0.12.6 ± 0.20.97 ± 0.0025 ± 40.42 ± 0.080.43 ± 0.08
Human0.52 ± 0.032.1 ± 0.10.96 ± 0.00
IbrutinibRat6.1 ± 0.115 ± 00.64 ± 0.0134 ± 50.094 ± 0.0330.15 ± 0.05
Dog8.4 ± 0.619 ± 10.33 ± 0.0254 ± 30.11 ± 0.110.34 ± 0.33
Monkey24 ± 126 ± 10.28 ± 0.0228 ± 50.0033 ± 0.00180.012 ± 0.006
Human15 ± 116 ± 00.076 ± 0.010
NeratinibRat0.43 ± 0.211.4 ± 0.70.96 ± 0.028.2 ± 1.30.21 ± 0.080.22 ± 0.08
Dog3.6 ± 0.1413 ± 00.70 ± 0.0132 ± 40.23 ± 0.050.33 ± 0.07
Monkey12 ± 118 ± 10.50 ± 0.0222 ± 40.014 ± 0.0100.028 ± 0.020
Human3.0 ± 0.68.5 ± 1.10.55 ± 0.06
  • a In vitro metabolic (intrinsic) clearance of afatinib, ibrutinib, and neratinib in hepatocytes suspended in 100% serum calculated by eq. 1 based on the data shown in Fig. 3.

  • b Predicted hepatic clearance calculated by eq. 2 and eq. 3.

  • c Predicted hepatic availability calculated by eq. 4.

  • d Observed total body (plasma) clearance calculated from plasma concentration–time curve after intravenous administration (1 mg/kg) shown in Fig. 4.

  • e Oral bioavailability calculated from AUC values after intravenous (1 mg/kg) and oral (3 mg/kg) administrations.

  • f Product of absorption fraction (fa) and intestinal availability (FG) calculated by eq. 8.