2. Overview of repeat dose toxicity and carcinogenicity studies, with kinetic data Report no. Study duration, Teriflunomide Cmax Teriflunomide AUC Main target organs / effects (date); GLP route; doses (µg/mL) at (µg.h/mL) at status teriflunomide respective doses respective doses (mg/kg/day) (CD-1) Male (M) / Female (F) 2004-0511 (Apr 3 months PO range 90 / 66 1660 / 1040 Haematopoietic tissues/organs 2006); GLP; day finding study; (bone marrow hypocellularity and 234 / 263 4520 /4880 85 kinetic data spleen necrosis/ atrophy); 0, 5, 25, 50, 75 239 / 261 (day 1) 4670 / 5090 (day 1) lymphoid tissues/organs (thymus and lymph node necrosis and 290 / 323 (day 1) 6140 / 6760 (day 1) atrophy); intestinal tract (degeneration/ regeneration /glandular necrosis/ulcer /inflammation); liver (hepatocyte centrilobular hypertrophy and (at fatal doses) single cell necrosis), reproductive organs (degeneration, atrophy). Deaths at 50 ≥ mg/kg/day. NOEL not established. CAR0092 (Jun 2 year PO 9.7 / 9.0 162 / 184 Skin (ulcer), GI tract (atrophic 201); GLP; day (carcinogenicity changes), thymus (atrophy), liver 57 / 48 1020 / 828 29 kinetic data (granuloma, inflammatory cell 232 / 204 3600 / 3120 infiltrate), bone marrow 0, 1, 4, 12 (granulopoiesis), heart (bacteria and thrombus), kidney (↑ incidence of chronic progressive nephropathy), generalised amyloidosis. mortality at 12 ↑
2. Overview of repeat dose toxicity and carcinogenicity studies, with kinetic data Report no. (date); GLP status Study duration, route; doses teriflunomide (mg/kg/day) Teriflunomide Cmax (µg/mL) at respective doses Teriflunomide AUC (µg.h/mL) at respective doses Main target organs / effects (CD-1) Male (M) / Female (F) 2004-0511 (Apr 2006); GLP; day 85 kinetic data 3 months PO range finding study; 0, 5, 25, 50, 75 90 / 66 234 / 263 239 / 261 (day 1) 290 / 323 (day 1) 1660 / 1040 4520 /4880 4670 / 5090 (day 1) 6140 / 6760 (day 1) Haematopoietic tissues/organs (bone marrow hypocellularity and spleen necrosis/ atrophy); lymphoid tissues/organs (thymus and lymph node necrosis and atrophy); intestinal tract (degeneration/ regeneration /glandular necrosis/ulcer /inflammation); liver (hepatocyte centrilobular hypertrophy and (at fatal doses) single cell necrosis), reproductive organs (degeneration, atrophy). Deaths at ≥ 50 mg/kg/day. NOEL not established. CAR0092 (Jun 201); GLP; day 29 kinetic data 2 year PO (carcinogenicity 0, 1, 4, 12 9.7 / 9.0 57 / 48 232 / 204 162 / 184 1020 / 828 3600 / 3120 Skin (ulcer), GI tract (atrophic changes), thymus (atrophy), liver (granuloma, inflammatory cell infiltrate), bone marrow (granulopoiesis), heart (bacteria and thrombus), kidney (↑ incidence of chronic progressive nephropathy), generalised amyloidosis. ↑ mortality at 12
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