6 months 5 0.14/0.6 [T07-10-06] 61 15 0.5/5 30 1.2/14 0 98 60 1.32/25.8 0.16/3 2/17 Dog 4 weeks 3 3.28 0.98 0.4 3 (Beagle) [T06-11-03] 10 20 4.67 2 13 20 50 8.1 6 23 6 months 0.5 1.12 0.61 0.13 2 [T07-10-07] 2.5 7.82 3.25 9 5 14.7 5.3 1.7 15 10 112 13 13 36 T08-07-03 0.75 0.95 0.35 0.11 1 [52 weeks] 1.5 2.5 0.74 0.3 2 3 5.5 1.3 0.6 4 6 17 4.4 2 12 steady state [25 mg bid] 8.5 0.36 – – aNo adequate data for the 350 mg/kg/day group; bFemale data only 3. Relative exposure to the human metabolites in pivotal toxicity studies Human Mouse Female rat Dog (6 month study) (6 month study) (52 week study) ha 125 mg/kg/day b 60 mg/kg/day b 6 mg/kg/day a µM.h AUC024h AUC024h ER AUC024 ER µM.h µM.h h AUC AUC µM.h Parent 8.5 64 8 30 4 17 2
6 months [T07-10-06] 5 0.14/0.6 15 0.5/5 30 1.2/14 60 1.32/25.8 0.16/3 2/17 Dog (Beagle) 4 weeks [T06-11-03] 3 3.28 0.98 0.4 3 10 20 4.67 2 13 20 50 8.1 6 23 6 months [T07-10-07] 0.5 1.12 0.61 0.13 2 2.5 7.82 3.25 9 5 14.7 5.3 1.7 15 10 112 13 13 36 T08-07-03 [52 weeks] 0.75 0.95 0.35 0.11 1 1.5 2.5 0.74 0.3 2 3 5.5 1.3 0.6 4 6 17 4.4 2 12 steady state [25 mg bid] 8.5 0.36 – – aNo adequate data for the 350 mg/kg/day group; bFemale data only 3. Relative exposure to the human metabolites in pivotal toxicity studies Human ha µM.h Mouse (6 month study) 125 mg/kg/day b Female rat (6 month study) 60 mg/kg/day b Dog (52 week study) 6 mg/kg/day a AUC024h µM.h AUC024h µM.h ER AUC AUC024 h µM.h ER AUC Parent 8.5 64 8 30 4 17 2 0 61 98