Table 3. Exposures to nintedanib in oral repeat dose toxicity and carcinogenicity studies. Exposure ratio# Exposure ratio# Study IPF indication NSCLC indication Dose duration time Cmax Species h of ng/mL Based Based Based Based ng∙h/mL measurement on on AUC on on AUC Cmax Cmax 10 56.95 228 1.8 0.63 1.3 0.42 13 weeks 30 251.5 1315 7.9 3.6 5.8 2.4 (Day 87) 100 1025 4735 32 13 24 8.8 5 18.75 40.15 0.59 0.11 0.43 0.07 15 82.2 340.5 2.6 0.94 1.9 0.63 (week 26) 30 261.5 1335 8.2 3.7 6.1 2.5 3 7.02 10.53 0.2 0.03 0.2 0.02 4 weeks (Day 20 52.25 134 1.6 0.4 1.2 0.3 28) 100 313 1545 9.8 4.3 7.3 2.9 3 2.14 5.35 0.1 0.01 0.1 0.01 13 weeks 20 62.6 216.5 2.0 0.6 1.5 0.4 (week 13) 100 246.5 1640 7.7 4.5 5.7 3.0 5 5.32 24.4 0.2 0.1 0.1 0.1 13 (Day Rat 20 31 179 1.0 0.5 0.7 0.3 87) 60 39.65 374 1.2 1.0 0.9 0.7 5 7.41 22.8 0.2 0.1 0.2 0.04 26 (Day 20 59.75 250 1.9 0.7 1.4 0.5 164-179) 80 170.5 1135 5.3 3.1 4.0 2.1 2.5 0.8935 1.66 0.03 0.005 0.02 0.003 5 4.935 25.85 0.15 0.07 0.11 0.05 (week 52) 10 9.83 82.95 0.31 0.23 0.23 0.15
Table 3. Exposures to nintedanib in oral repeat dose toxicity and carcinogenicity studies. Species Study duration time of measurement Dose Cmax ng/mL h ng∙h/mL Exposure ratio# IPF indication Exposure ratio# NSCLC indication Based on Cmax Based on AUC Based on Cmax Based on AUC 13 weeks (Day 87) 10 56.95 228 1.8 0.63 1.3 0.42 30 251.5 1315 7.9 3.6 5.8 2.4 100 1025 4735 32 13 24 8.8 (week 26) 5 18.75 40.15 0.59 0.11 0.43 0.07 15 82.2 340.5 2.6 0.94 1.9 0.63 30 261.5 1335 8.2 3.7 6.1 2.5 Rat 4 weeks (Day 28) 3 7.02 10.53 0.2 0.03 0.2 0.02 20 52.25 134 1.6 0.4 1.2 0.3 100 313 1545 9.8 4.3 7.3 2.9 13 weeks (week 13) 3 2.14 5.35 0.1 0.01 0.1 0.01 20 62.6 216.5 2.0 0.6 1.5 0.4 100 246.5 1640 7.7 4.5 5.7 3.0 13 (Day 87) 5 5.32 24.4 0.2 0.1 0.1 0.1 20 31 179 1.0 0.5 0.7 0.3 60 39.65 374 1.2 1.0 0.9 0.7 26 (Day 164-179) 5 7.41 22.8 0.2 0.1 0.2 0.04 20 59.75 250 1.9 0.7 1.4 0.5 80 170.5 1135 5.3 3.1 4.0 2.1 (week 52) 2.5 0.8935 1.66 0.03 0.005 0.02 0.003 5 4.935 25.85 0.15 0.07 0.11 0.05 10 9.83 82.95 0.31 0.23 0.23 0.15
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