TABLE 6

Effects of the change in F_{a, i}, F_{g, i}, f_{u, mic}, and f_{p, i} on the prediction of -fold increase in AUC (AUC_{s, day15}/AUC_{s, day1}) for plasma midazolam concentrations after repeated oral administration of FK1706 (60 mg) using a dynamic model developed in this study and in vitro CYP3A4/5 inactivation rate (k_{inact, vitro} and K_{I, vitro} and set of k_{deg, g} 0.0210 h⁻¹ and k_{deg, h} 0.00495 h⁻¹)

The values in the parentheses represent f_{u, mic, i, 0.05 mg/ml} corresponding to the values of f_{u, mic, i, 0.3 mg/ml} (Hallifax and Houston, 2006; Gertz et al., 2008). Observed AUC_{s, day15}/AUC_{s, day1} was 2.

Parameter as Variable	Predicted AUC_{s, day15}/AUC_{s, day1}
	Final Model: TDI Intestine and Liver, Direct Intestine Inhibition	Sensitivity Analysis (Contribution of Each Dimension of the Inhibition)
		TDI Liver	Direct Intestine Inhibition	TDI Intestine	TDI Intestine, Direct Intestine Inhibition	TDI Intestine and Liver
F_{a, i}
0.1	1.43	1.08	1.06	1.28	1.32	1.39
0.2	1.63	1.14	1.10	1.37	1.43	1.56
0.5	2.08	1.36	1.20	1.45	1.53	1.98
1^a	2.81	1.78	1.31	1.49	1.58	2.33
F_{g, i}
0.1	1.70	1.08	1.31	1.49	1.58	1.61
0.2	1.80	1.14	1.31	1.49	1.58	1.70
0.5	2.15	1.36	1.31	1.49	1.58	2.03
1^a	2.81	1.78	1.31	1.49	1.58	2.33
f_{u, mic, i, 0.3} _mg/ml
0.1 (0.4)	8.54	5.31	1.42	1.53	1.61	8.15
0.2 (0.6)	5.20	3.26	1.36	1.52	1.60	4.96
0.528^a (0.87)	2.81	1.78	1.31	1.49	1.58	2.33
1 (1)	2.16	1.39	1.28	1.46	1.55	2.02
f_{p, i}
0.005	2.18	1.38	1.31	1.49	1.58	2.07
0.01^a	2.81	1.78	1.31	1.49	1.58	2.33
0.02	4.13	2.62	1.31	1.49	1.58	3.91
0.05	7.66	4.86	1.31	1.49	1.58	7.25

↵a Default values.