dosage group received two divided doses rather than a single daily dose. This is not expected to significantly affect the validity of the toxicity studies. Paritaprevir was administered with the CYP3A4 inhibitor ritonavir as a pharmacokinetic booster. The doses of ritonavir in the repeat dose toxicity studies were selected to optimise exposure to paritaprevir for each nonclinical species, and were capped at this level to enable paritaprevir toxicity to be explored without being confounded by ritonavir toxicity. Doses of paritaprevir were generally acceptable, achieving high relative exposures to paritaprevir (see Table 3 and Figure 6). In the earlier studies in rats, saturation of plasma exposure to paritaprevir was identified as limiting the usefulness of this species, and so the CD-1 mouse was chosen to be the rodent species for the remainder of the toxicology programme. Table 3: Relative exposure Species Study Analyte Dose AUC0–24 h Exposure duration (mg/kg/day) (µg∙h/mL) ratio# Mouse 4 weeks 30 51 7.3 (Day 28) 100 131 19 300 344 49 450 421 60 Ritonavir 30 49.5 5.2 6 months 6 1.56 0.22 60 121 17 (Day 87) 300 269 38 Ritonavir 30 44.5 4.7 Mouse 6 months 30 33.5 4.8 1) (Day 182) 100 220 32 300 305 44 Ritonavir 30 30.4 3.2 Rat (SD) 1 day 500 33.1 4.7 1000 87.1 12 2000 83.3 12 13 100 73.9 11 (Day 87) 300 104.4 15 450 91.4 13
dosage group received two divided doses rather than a single daily dose. This is not expected to significantly affect the validity of the toxicity studies. Paritaprevir was with the CYP3A4 inhibitor ritonavir as a pharmacokinetic booster. The doses of ritonavir in the repeat dose toxicity studies were selected to optimise exposure to paritaprevir for each nonclinical species, and were capped at this level to enable paritaprevir toxicity to be explored without being confounded by ritonavir toxicity. Doses of paritaprevir were generally acceptable, achieving high relative exposures to paritaprevir (see Table 3 and Figure 6). In the earlier studies in rats, saturation of plasma exposure to paritaprevir was identified as limiting the usefulness of this species, and so the CD-1 mouse was chosen to be the rodent species for the remainder of the toxicology programme. Table 3: Relative exposure Species Study duration Analyte Dose (mg/kg/day) AUC0–24 h (µg∙h/mL) Exposure ratio# Mouse 4 weeks (Day 28) 30 51 7.3 100 131 19 300 344 49 450 421 60 Ritonavir 30 49.5 5.2 6 months (Day 87) 6 1.56 0.22 60 121 17 300 269 38 Ritonavir 30 44.5 4.7 Mouse 6 months (Day 182) 30 33.5 4.8 100 220 32 300 305 44 Ritonavir 30 30.4 3.2 Rat (SD) 1 day 500 33.1 4.7 1000 87.1 12 2000 83.3 12 13 (Day 87) 100 73.9 11 300 104.4 15 450 91.4 13 administered 1)
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