TABLE 2

Outlines of bosutinib PBPK modeling for model refinement, verification, and application

PBPK Model^{^a}	Approach	Bosutinib Dose (mg)	Precipitant Drug	Clinical Studies Used	Key Parameters Explored
IV	Refinement	120^{^b}	−	F_oral	CL_int and V_ss
F_a	Refinement	500	−	F_oral	f_u,gut
	Verification	100 and 500	Ketoconazole	DDI	C_maxR and AUCR
		500	Rifampin	DDI	C_maxR and AUCR
ADAM	Refinement	500	−	F_oral	P-gp kinetics (J_max SF)^{^c}
		100 and 500	−	DDI^{^d}	P-gp kinetics (J_max SF)^{^c}
	Verification	100 and 500	Ketoconazole	DDI	P-gp inhibition (K_i)^{^e}
		500	Rifampin	DDI	P-gp induction (abundance)^{^f}
	Application	500	Itraconazole	−	DDI prediction
		500	Verapamil	−	DDI prediction

−, not applicable.
↵^a PBPK model without absorption model (PBPK-IV), PBPK model with the first order absorption model (PBPK-F_a), and PBPK model with the ADAM model using P-gp kinetic parameters (PBPK-ADAM).
↵^b Single intravenous 1-hour infusion.
↵^c In vitro-to-in vivo scaling factor (SF) for intestinal P-gp J_max.
↵^d Control groups (bosutinib alone) of the DDI study with ketoconazole (100 and 500 mg) and rifampin (500 mg).
↵^e Ketoconazole K_i for intestinal P-gp.
↵^f Rifampin-mediated increases in intestinal P-gp abundance.