TABLE 3

Four-day multiple-dose pharmacokinetics of endoxifen in fasted and fed female beagle dogs

Route	I.V.		P.O.
Dose (mg/kg)	0.5		15		30		100		100
Fed/Fasted	Fasted								Fed
Dog I.D.	5F9841	5F9845	1F9839	1F9842	2F9845	2F9846	3F9844	3F9847	6F9840	6F9849
Day 1
C_max (ng/mL)	633	905	2111	1717	2548	3903	4527	10850	4590	3250
Half-life (h)	7.6	5.8	3.1	8.3	13.8	9.1	8.9	7.3	8.3	7.2
AUC_0-24 (ng/mL*h)	1392	892	16189	18481	14751	38059	49178	170254	69376	51100
AUC_0-∞ (ng/mL*h)	1579	892	22237	23262	21684	46732	134409	196880	80554	58395
Cl_app (L/h per kg)	0.32	0.56	0.67	0.64	1.4	0.64	0.74	0.51	1.2	1.7
Absolute bioavailability^a	N/A	N/A	59.4	62.1	29.1	62.8	54.4	79.7	79.7	23.6
Day 4
C_max (ng/mL)	228	129	825	2938	8979	8604	N/A	N/A	N/A	N/A
Half-life (h)	4.8	12.2	29.2	8.1	5.8	10.2	N/A	N/A	N/A	N/A
AUC_0-24 (ng/mL*h)	1406	356	11805	29514	83958	80895	N/A	N/A	N/A	N/A
AUC_0-∞ (ng/mL*h)	1453	487	29679	34872	89818	105027	N/A	N/A	N/A	N/A
Cl_app (L/h per kg)	0.34	1.0	0.5	0.43	0.33	0.29	N/A	N/A	N/A	N/A
Absolute bioavailability	N/A	N/A	101	117	154	180	N/A	N/A	N/A	N/A

AUC_0-∞, area under the concentration-time curve from zero up to ∞ with extrapolation of the terminal phase; CL_app, apparent clearance; I.D., identification; N/A, not available.
^aAbsolute bioavailability was calculated using the following equation: ((AUC_0-∞)p.o_{. dose}/(Avg. AUC_0-∞)_{I.V. dose}) × ((0.5-mg/kg i.v. dose)/(p.o. dose mg/kg)) × 100%.