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
mg/kg/day. NOAEL 1 mg/kg/day. No neoplastic findings. Rat M / F 017716 (Jun 1999); GLP; day 30 kinetic data 3 months PO in Wistar rats; 0, 0.5, 1, 4 2.4 / 2.8 4.7 / 5.7 17 / 21 35 / 38 71 / 70 217 / 202 Red blood cell parameters (marginal ↓), liver (marginal ↑ in weight) at HD. NOAEL 4 mg/kg/day. 2003-1492 (Sep 2005); GLP; day 181 kinetic data 6 months PO in SD rats; 0, 0.3, 1.5 (↑ to 9 at week 15), 3, 6 1.5 / 1.8 8.6 / 9.4 (day 90) and 40 / 49 20 / 21 33 / 33 26 / 29 102 / 124 (day 90) and 487 / 568 240 / 330 342 / 418 Atrophic changes in haematopoietic tissues/organs, spleen; lymphoid tissues/organs; intestinal tract and reproductive tissues; liver (hepatocyte focal and (mainly at fatal doses) single cell necrosis). Deaths at 9 mg/kg/day. NOEL 0.3 mg/kg/day. 95.0170 (Mar 1995); GLP Previously evaluated 4 week IV study in Wistar rats; 0, 3.2, 8, 20 N/A [C24 h (µg/mL) data: 1.5; 1.2; ≤ 1.8] As above, and additional toxicity associated with Baccilus piliformis infection, and one case of CNS haemorrhage (not associated with infection). Deaths at all doses (attributed to hepatic disease). NOEL not established.
95.0288 (May 1995); GLP Second previously evaluated 4 week IV in Wistar rats; 0, 0.25, 1 N/A [Mean concentration 1.1-5.1 µg/mL at various time-points over 0.5-24 h] Deaths in HD rats (changes as described including cerebellar haemorrhage; attributed to Baccilus piliformis infection). No effects in rats surviving the HD. NOEL 0.25 mg/kg/day. (Sep 2009); GLP; day 169 kinetic data 2 year PO (carcinogenicity in SD rats; 0, 0.5, 1.5, 4 3 / 4 9 / 11 20 / 27 51 / 60 104 / 148 275 / 329 Bone marrow (hypocellularity, decrease in hematopoietic cells), submandibular lymph node (decreased plasmacytosis), spleen (decreased lymphocytes and increased pigment (hemosiderin), liver (↑ focus of cellular alteration, hypertrophy, multinucleated hepatocytes). Mortality ↑ at MD and HD (♂ only). NOEL not established. Dog (beagle) M / F 017737 (Jul 1999); GLP; day 88 kinetic data 3 month PO; 0, 0.8, 2.5, 8 6.4 / 6.7 51 / 34 103 / 72 (day 23) 107 / 118 680 / 590 1673 / 1185 (day 23) Atrophic changes in haematopoietic tissues/organs, spleen; intestinal tract and oral mucosae; and ↑ siderin storage in liver Kupffer cells. Deaths at HD. NOEL 0.8 mg/kg/day. trial