4 Weeks 30 5.29 ≈2 ≈0.5 100 17.7 ≈5 ≈2 Dog IV (Beagle) infusion 150/200 56.3 ≈16 ≈5 4 Weeks 300 ≈16.7 ≈5 ≈1 PO 600 ≈51 ≈15 ≈4 Monkey 900 ≈106.3 ≈30 ≈9 39 300 ≈18.7 ≈5 ≈2 PO 600 ≈79.3 ≈23 ≈7 Monkey 900 ≈165 ≈47 ≈15 * at study termination unless otherwise noted; # Healthy volunteer data from Study No. N01109 for 200 mg PO dose AUC= 3.51 severe renal impairment data - AUC= 11.4 Study NOEL or – μg.h/mL, μg.h/mL; ˢ NOAEL. Relative exposure margins for metabolite ucb-100406-1 in adults In general adequate levels of systemic exposure for ucb-100406-1 were achieved in the nonclinical studies in comparison with the expected level of human systemic exposure at the MHRD for both normal patients and patients with severe renal impairment. Table 11: Relative exposure margins for metabolite ucb-100406-1. Study Study Exposure Species duration or ratio in ratio in Route Dose normal humans (mg/kg/ humans# with day) severe renal PSM1256 13 Weeks 450 ♂=185ˢ; ♂≈13; ♂≈3; ♀≈3 ♀=164 ♀≈12 Mouse PO (CD-1) 675 ♂=300; ♂≈21 ♂≈5; ♀≈5 ♀=289 ♀≈21 1000 ♂=403; ♂≈29; ♂≈7; ♀≈8 ♀=456 ♀≈32 NCD1304 104 400 ♂=155ˢ; ♂≈11; ♂≈3; ♀≈3 Weeks ♀=148 ♀≈11 Mouse (CD-1) PO 550 ♂=241; ♂≈17; ♂≈4; ♀≈4 ♀=237 ♀≈17 700 ♂=314; ♂≈22; ♂≈6; ♀≈6 ♀=341 ♀≈24
Dog (Beagle) 4 Weeks IV infusion 30 5.29 ≈2 ≈0.5 100 17.7 ≈5 ≈2 150/200 56.3 ≈16 ≈5 Monkey 4 Weeks PO 300 ≈16.7 ≈5 ≈1 600 ≈51 ≈15 ≈4 900 ≈106.3 ≈30 ≈9 Monkey 39 PO 300 ≈18.7 ≈5 ≈2 600 ≈79.3 ≈23 ≈7 900 ≈165 ≈47 ≈15 * at study termination unless otherwise noted; # Healthy volunteer data from Study No. N01109 for 200 mg PO dose – AUC= 3.51 μg.h/mL, severe renal impairment data - AUC= 11.4 μg.h/mL; ˢ Study NOEL or NOAEL. Relative exposure margins for metabolite ucb-100406-1 in adults In general adequate levels of systemic exposure for ucb-100406-1 were achieved in the nonclinical studies in comparison with the expected level of human systemic exposure at the MHRD for both normal patients and patients with severe renal impairment. Table 11: Relative exposure margins for metabolite ucb-100406-1. Study Species Study duration Route Dose (mg/kg/ day) or ratio in normal humans# Exposure ratio in humans with severe renal PSM1256 Mouse (CD-1) 13 Weeks PO 450 ♂=185ˢ; ♀=164 ♂≈13; ♀≈12 ♂≈3; ♀≈3 675 ♂=300; ♀=289 ♂≈21 ♀≈21 ♂≈5; ♀≈5 1000 ♂=403; ♀=456 ♂≈29; ♀≈32 ♂≈7; ♀≈8 NCD1304 Mouse (CD-1) 104 Weeks PO 400 ♂=155ˢ; ♀=148 ♂≈11; ♀≈11 ♂≈3; ♀≈3 550 ♂=241; ♀=237 ♂≈17; ♀≈17 ♂≈4; ♀≈4 700 ♂=314; ♀=341 ♂≈22; ♀≈24 ♂≈6; ♀≈6