TABLE 1

Prediction from hepatocytes [hepatic clearance (CL_H) and availability (F_H)] and observed pharmacokinetics in preclinical species [total body (plasma) clearance (CL_tot,obs), oral bioavailability (F_PO), and absorption fraction × intestinal availability (f_a⋅F_G)]

Data represent mean ± S.D. (n = 3).

Drug	Species	CL_{int,in vitro}^{^a}	Predicted CL_H^{^b}	Predicted F_H^{^c}	CL_tot,obs^{^d}	F_PO^{^e}	f_a⋅F_G^{^f}
		µl/min/10⁶ cells	ml/min/kg		ml/min/kg
Afatinib	Rat	0.71 ± 0.03	2.3 ± 0.1	0.99 ± 0.00	90 ± 10	0.38 ± 0.16	0.39 ± 0.16
	Dog	1.7 ± 0.2	7.6 ± 0.6	0.96 ± 0.00	64 ± 3	0.81 ± 0.01	0.85 ± 0.01
	Monkey	1.1 ± 0.1	2.6 ± 0.2	0.97 ± 0.00	25 ± 4	0.42 ± 0.08	0.43 ± 0.08
	Human	0.52 ± 0.03	2.1 ± 0.1	0.96 ± 0.00
Ibrutinib	Rat	6.1 ± 0.1	15 ± 0	0.64 ± 0.01	34 ± 5	0.094 ± 0.033	0.15 ± 0.05
	Dog	8.4 ± 0.6	19 ± 1	0.33 ± 0.02	54 ± 3	0.11 ± 0.11	0.34 ± 0.33
	Monkey	24 ± 1	26 ± 1	0.28 ± 0.02	28 ± 5	0.0033 ± 0.0018	0.012 ± 0.006
	Human	15 ± 1	16 ± 0	0.076 ± 0.010
Neratinib	Rat	0.43 ± 0.21	1.4 ± 0.7	0.96 ± 0.02	8.2 ± 1.3	0.21 ± 0.08	0.22 ± 0.08
	Dog	3.6 ± 0.14	13 ± 0	0.70 ± 0.01	32 ± 4	0.23 ± 0.05	0.33 ± 0.07
	Monkey	12 ± 1	18 ± 1	0.50 ± 0.02	22 ± 4	0.014 ± 0.010	0.028 ± 0.020
	Human	3.0 ± 0.6	8.5 ± 1.1	0.55 ± 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 (f_a) and intestinal availability (F_G) calculated by eq. 8.