TABLE 7

PBPK-ADAM model-predicted pharmacokinetic parameters of bosutinib in bosutinib 500-mg single-dose DDI studies with verapamil and itraconazole

Data are expressed as geometric mean with percent coefficient of variation (CV%) except for C_maxR and AUCR with 90% confidence interval in parentheses (n = 6 per group × 6 groups for the predicted).

PBPK Model	Precipitant Drug	Group^{^a}	K_i^{^b}	C_max	AUC	C_maxR^{^c}	AUCR^{^c}
PBPK Model	Precipitant Drug	Group^{^a}	μM	ng/ml	ng⋅h/ml	ratio	ratio
ADAM	Itraconazole	Control	−	114 (51)	2578 (71)	−	−
		Test	−	228 (46)	21,108 (123)	2.0 (1.9–2.1)	8.5 (6.5–10)
			0.5	229 (46)	21,159 (123)	2.0 (1.9–2.1)	8.5 (6.5–10)
	Verapamil	Control	−	112 (49)	2528 (70)	−	−
		Test	−	190 (50)	11,269 (110)	1.7 (1.6–1.8)	4.5 (3.7–5.3)
			0.16	226 (49)	13,015 (111)	2.0 (1.9–2.2)	5.1 (4.3–6.2)

−, not applicable.
↵^a Bosutinib 500 mg without and with itraconazole 200 mg once daily (control and test groups, respectively) or verapamil 80 mg three times a day.
↵^b K_i for intestinal P-gp.
↵^c Ratios of C_max and AUC in test group relative to control group.