Table III.

Summary of Crizotinib Pharmacokinetic and Pharmacodynamic Parameters for the Projection of Crizotinib-Mediated ALK and MET-Inhibition in Patients

Species	Target	Dosea	CL/F b	V/F b	k a b	k e0 b	EC 50,total b	EC 50,free	f u,plasma
		mg/kg/day	L/h/kg	L/kg	h −1	h −1	ng/mL	ng/mL
Xenograft	ALK	25 to 200	1.9 to 4.4	1.0 to 17	0.1 to 1.8	0.030	233	8.4	0.036
	MET	6.3 to 50	1.5 to 14	3.2 to 56	0.24 to 0.34	0.135	18.5	0.67
Patients	ALK	7.1	1.0	21	0.75	0.030	90	8.4	0.093
	MET					0.135	7.2	0.67

^aDaily dose in patients was calculated from clinically recommended dose (500 mg/day) with a body weight of 70 kg

^bPharmacodynamic parameters in xenograft models were estimated in athymic nu/nu mice bearing H3122 NSCLC (ALK) or GTL16 GC (MET). Results are cited from previous reports (21,22). Pharmacokinetic parameters in patients were adjusted from the clinically observed single-dose PK parameters to simulate comparable steady-state plasma concentrations to the clinically observed results previously reported (30). The EC _50,total values in patients were calculated from those estimated in the xenograft models following the correction for the difference in unbound fraction in plasma (f _u,plasma) between mice and humans. Other pharmacodynamic parameters such as E _max, E ₀ and γ were fixed as unity for the simulation in patients