TABLE 1

Physicochemical and pharmacokinetic parameters of crizotinib used for PBPK model

Parameters (Units)		Parameters (Units)
Molecular weight	450	CL_int (μl/min per milligram protein)^{^c}
logP	4.29	CL_int,CYP3A4	103–177
pK_a	5.4 and 8.9	CL_int,others	26–44
f_u,plasma	0.093	CL_renal (l/h)	2.25
R_bp	1.1	Time-dependent inhibition on CYP3A
F_a	0.3–0.5	K_I (μM)	0.89
k_a (h⁻¹)^{^a}	0.01–0.3	k_inact (h⁻¹)	0.78
Q_gut (l/h)	4.0	CYP3A4 induction
f_u,gut^{^b}	0.085	E_max (fold)	2.4
V_ss (l/kg)	25	EC₅₀ (μM)	0.84

R_bp, blood-to-plasma ratio.
↵^a The value of k_a was adjusted to simulate the clinically observed t_max of approximately 4 hours.
↵^b The value of f_u,gut was assumed as f_u,blood calculated by f_u,plasma and R_bp.
↵^c The values of CL_int in human liver microsomes were back-calculated from the clinically observed CL estimates using a retrograde model implemented in Simcyp.