TABLE 3

DDI predictions based on in vitro IC₅₀ values and the FDA’s recommended basic and static models

Transporter	Clinical CYP3A4/5 Inhibitors
Transporter	Ketoconazole	Clarithromycin	Ritonavir	Itraconazole	Hydroxy-itraconazole	Keto-itraconazole	N-Desalkyl-itraconazole	Itraconazole + Metabolites
[I]₁ (C_max,t)/IC₅₀ (≥0.1 indicates potential for clinically relevant interaction)
P-gp	0.51	0.35	15	24	1.3	0.19	0.0022	25
BCRP	0.23	NC	0.53	0.60	1.4	0.24	NC	2.2
BSEP	1.2	0.053	0.57	0.65	10	0.20	NC	11
MRP2	NC	NC	NC	NC	NC	NC	NC	0.00
MRP3	NC	NC	NC	NC	NC	NC	NC	0.00
OATP1B1	1.6	0.59	5.1	NC	2.7	0.08	NC	2.8
OATP1B3	0.72	0.22	1.5	NC	6.0	0.26	NC	6.2
OCT1	21	NC	0.85	1.6	55	2.1	NC	59
R values (≥1.25 indicates potential for clinically relevant interaction)
OATP1B1	1.95	3.5	1.2	NC	1.0	1.0	NC	1.03
OATP1B3	1.44	2.0	1.1	NC	1.0	1.0	NC	1.04
Unbound C_max/IC₅₀ (>0.1 indicates potential for clinically relevant interaction)
OAT1	0.016	NC	0.0041	NC	NC	NC	NC	NC
OAT3	0.11	NC	NC	NC	0.0022	NC	NC	0.0022
OCT1	0.67	NC	0.017	0.056	0.28	0.11	NC	0.44
OCT2	0.10	NC	NC	NC	NC	NC	NC	NC
MATE1	0.25	NC	0.060	NC	0.73	0.022	NC	0.75
MATE2-K	NC	NC	0.0046	NC	NC	NC	NC	NC
P-gp	0.016	0.10	0.29	0.87	0.011	0.010	0.00003	0.88
BCRP	0.007	NC	0.010	0.022	0.011	0.013	NC	0.04
[I]₂/IC₅₀ (≥10 indicates potential for clinically relevant interaction)
P-gp	541	301	2332	11,860	NA	NA	NA	NA
BCRP	246	NC	84	294	NA	NA	NA	NA
MRP2	NC	NC	NC	NC	NA	NA	NA	NA

NC: Not calculated. No inhibition observed or the IC₅₀ value was greater than the highest concentration tested. NA: Not applicable. Exposure of intestinal efflux transporters to itraconazole metabolites assumed to be negligible upon oral dosing of itraconazole. R value = 1 + (fu × I_inlet,max/IC₅₀) (FDA, 2012; and references within). [I]₂ = dose/250 mL. C_max and fraction unbound values listed in Table 2. Summation of itraconazole and its metabolites adapted from approach used by Templeton et al., 2010.