[Pivotal 200 40.8 29 toxicity] Study No. R&D/11/561 female 10 3.38 2.4 Sampling day: 40 17.9 12.6 182 200 32.1 23 Rat [SD] 3 month male/ 10 10.7/9.2 7.5/6.5 female No. [Pivotal 30 20.4/25.4 14.4/18 R&D/10/1472 toxicity] 300 22.4/35.3 16/25 Sampling day: 91 Dog [Beagle] 6 month male/ 4 8.5/6 6/4.2 female Study No. [Pivotal 20 54/41.5 38/29 R&D/10/1371 toxicity] 100 90/77 63.4/58.2 Sampling day: 189 Study R&D/14/0500 Steady state 25 mg/day 1.42 – – Human (healthy volunteers) # = animal:human plasma AUC0–24 h ; Bolded = NOAEL Also exposures attained in mouse toxicity studies on human metabolites M29 (A1538855) and M36 (A-1548255) were adequate multiples of levels reported in human subjects (> 20 times clinical AUC levels). Relative exposure is summarised in Table 6. 6: Relative exposure to ombitasvir metabolites M29 and M36 in mouse toxicity studies - ombitasvir Study details Dose (mg/kg/day) AUC0–24 h Exposure (µg.h/mL) ratio# Study No. R&D/13/760 1 3.49 5.2 2 7.03 10.5 4 week repeat dose toxicity 3.5/3.0 15.8/18.1 24/27 [M29; Clinical AUC: 0.669 µg.h/mL] No. R&D/13/701 1.5 3.07 7 3 6.55 15 4 week repeat dose toxicity 6 16.8 38
Study No. R&D/11/561 [Pivotal toxicity] Sampling day: 182 200 40.8 29 female 10 3.38 2.4 40 17.9 12.6 200 32.1 23 Rat [SD] No. R&D/10/1472 3 month [Pivotal toxicity] Sampling day: 91 male/ female 10 10.7/9.2 7.5/6.5 30 20.4/25.4 14.4/18 300 22.4/35.3 16/25 Dog [Beagle] Study No. R&D/10/1371 6 month [Pivotal toxicity] Sampling day: 189 male/ female 4 8.5/6 6/4.2 20 54/41.5 38/29 100 90/77 63.4/58.2 Study R&D/14/0500 Human (healthy volunteers) Steady state – 25 mg/day 1.42 – # = animal:human plasma AUC0–24 h ; Bolded = NOAEL Also exposures attained in mouse toxicity studies on human metabolites M29 (A1538855) and M36 (A-1548255) were adequate multiples of levels reported in human subjects (> 20 times clinical AUC levels). Relative exposure is summarised in Table 6. 6: Relative exposure to ombitasvir metabolites M29 and M36 in mouse toxicity studies - ombitasvir Study details Dose (mg/kg/day) AUC0–24 h (µg.h/mL) Exposure ratio# Study No. R&D/13/760 4 week repeat dose toxicity [M29; Clinical AUC: 0.669 µg.h/mL] 1 3.49 5.2 2 7.03 10.5 3.5/3.0 15.8/18.1 24/27 No. R&D/13/701 4 week repeat dose toxicity 1.5 3.07 7 3 6.55 15 6 16.8 38