Table 5. Repeat dose toxicity studies; exposure relative to hepatically impaired patients Species Study Dose Cmax Cmax AUC0-24 AUC duration h ng.h/mL Exposure ng/mL (weeks) ratioa ratioa (m/f) (m/f) Repeat dose toxicity studies Mouse 28 days 250 0.5/0.7 95.9/117 0.7/0.9 1000 0.5/0.6 69.9/176 0.5/1.3 2000 0.6/1.2 88.4/215 0.7/1.6 Rat Day 1 of 5 14.21 0.7 50.65 0.4 26 week 150 20.83 1.0 92.35 0.7 study 300 25.04 1.2 126.7 1.0 Dog 39 week 100 16.97 0.8 61.35 0.5 300 21.82 1.0 75.45 0.6 1000 21.88 1.0 105.7 0.8 Dog 4 week 1000 7/10 0.3/0.5 80/113 0.6/0.9 300 91/68 67/71 (amorp.) 1000 95/55 (amorp.) a Exposure trial based on human study with hepatically impaired patients (550 mg twice daily: Cmax 21.1 ng/mL; AUCtau 130 ng.h/mL (Study no. RFHE 3002PK). Table 6. Embryofetal development; exposure relative to healthy volunteers Species Study Dose Cmax Cmax AUC 0-24 AUC Exposure ng·h/ml ratioa ratioa PO (gavage) Rabbit 62.5 ND - ND - toxicity 250 1.7 0.5 8.3 0.7
Table 5. Repeat dose toxicity studies; exposure relative to hepatically impaired patients Species Study duration (weeks) Dose Cmax ng/mL (m/f) Cmax ratioa AUC0-24 h ng.h/mL (m/f) AUC Exposure ratioa Repeat dose toxicity studies Mouse 28 days 250 0.5/0.7 95.9/117 0.7/0.9 1000 0.5/0.6 69.9/176 0.5/1.3 2000 0.6/1.2 88.4/215 0.7/1.6 Rat Day 1 of 26 5 14.21 0.7 50.65 0.4 week study 150 20.83 1.0 92.35 0.7 300 25.04 1.2 126.7 1.0 Dog 39 week 100 16.97 0.8 61.35 0.5 300 21.82 1.0 75.45 0.6 1000 21.88 1.0 105.7 0.8 Dog 4 week 1000 7/10 0.3/0.5 80/113 0.6/0.9 300 (amorp.) 91/68 67/71 1000 (amorp.) 95/55 a Exposure based on human study with hepatically impaired patients (550 mg twice daily: Cmax 21.1 ng/mL; AUCtau 130 ng.h/mL (Study no. RFHE 3002PK). Table 6. Embryofetal development; exposure relative to healthy volunteers Species Study Dose PO (gavage) Cmax Cmax ratioa AUC 0-24 ng·h/ml AUC Exposure ratioa Rabbit toxicity 62.5 ND - ND - 250 1.7 0.5 8.3 0.7 trial
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