TABLE 5

Prediction of drug-drug interactions between paclitaxel and kinase inhibitors based on reversible inhibition

Inhibitors	R_2C8 (1+I/K_i,2C8)	R_3A4 (1+I/K_i,3A4)	AUC_ratio(Ignoring EH)^{^a}	AUC_ratio^{^b}				Observed AUC_ratio^{^c}
Inhibitors	R_2C8 (1+I/K_i,2C8)	R_3A4 (1+I/K_i,3A4)	AUC_ratio(Ignoring EH)^{^a}	EH = 0.1^{^d}	EH = 0.5^{^d}	EH = 0.9^{^d}	EH = 0.78^{^e}	Observed AUC_ratio^{^c}
Afatinib	1.00	1.00	1.04	1.00	1.00	1.00	1.00	0.86
Axitinib	1.54	1.04	1.52	1.40	1.22	1.04	1.10	1.04
Bosutinib	1.21	3.90	1.35	1.26	1.14	1.03	1.06	—
Dasatinib	1.03	1.07	1.07	1.03	1.01	1.00	1.01	0.86
Erlotinib	1.99	4.10	2.17	1.91	1.51	1.10	1.22	0.97
Gefitinib	1.10	1.19	1.15	1.10	1.05	1.01	1.02	—
Imatinib	2.00	2.47	2.12	1.87	1.48	1.10	1.21	—
Lapatinib	4.70	2.38	4.43	3.54	2.41	1.28	1.61	—
Nilotinib	31.12	11.76	27.64	12.57	7.43	2.29	3.78	—
Pazopanib	10.83	38.70	12.13	7.70	4.72	1.74	2.61	43% increase in C_max
Sorafenib	6.83	3.25	6.37	4.76	3.09	1.42	1.90	—
Sunitinib	1.00	1.01	1.04	1.00	1.00	1.00	1.00	1.30

↵^a A static model incorporating parallel pathways was used (Ito et al., 2005; Lu et al., 2008). The EH of paclitaxel was not incorporated.
↵^b A static model described by Kirby and Unadkat (2010) was used by incorporating parallel pathways and with the consideration of paclitaxel EH.
↵^c Observed AUC_ratio was estimated based on literature reports (Table 1) where AUC values were available.
↵^d Arbitrary EH values were assigned and used for comparison purposes.
↵^e The EH value of paclitaxel was estimated based on literature data (Smorenburg et al., 2003) as described in Materials and Methods.