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)
Embryofetal development (main GD17 RTV 15 8.46 0.9 PAR 100 45.2 65 RTV 15 8.22 0.9 PAR 450 58.6 8 RTV 45 26.2 2.8 Mouse CD-1 Embryofetal development (main study) GD15 PAR 30 224 32 PAR 100 631 90 PAR 300 686 98 RTV 30 49.7 5.2 Rat (Crl:CD1[ICR]) Pre/postnatal development PAR 30 0.345* 0.05 RTV 30 18.1* 1.9 PAR 60 5.36* 0.8 RTV 30 20.2* 2 PAR 300 116* 17 RTV 30 17* 1.8 Human (healthy volunteers) steady PAR 150 mg/day 6.99 – Human (healthy volunteers) steady state RTV 100 mg/day 9.47 - # = animal: human plasma AUC0–24 h. * = maternal plasma AUC Pregnancy classification The sponsor has proposed Pregnancy Category B1 for paritaprevir. The reference regarding animal data in the pregnancy category statement for B1 is consistent with the results from the nonclinical assessment. This category would be appropriate if the clinical data indicates that paritaprevir has indeed been taken by a limited number of pregnant women and women of childbearing age without an evidence of an increase in the frequency of malformation or indirect harmful effects. When combined with ritonavir (Pregnancy Category B3) or ribavirin (Pregnancy Category X) then the higher pregnancy category takes precedence. This is discussed in the evaluation of the combination products Viekira Pak and Viekira Pak–RBV. Photosafety No nonclinical phototoxicity studies have been submitted based on supporting clinical safety information from Phase III clinical studies. Although paritaprevir absorbs light in the
CYP3A4 substrate AUC increased by 57% when with ketoconazole; AUC decreased by 87% when with carbamazepine P-gp, P-gp substrate; No active uptake by OATP1B1/3 expressed in HEK cells Ctrough concentrations increased by 40-49% when co-administered with cyclosporine and atazanavir CYP3A4 Km2 = 71 µM; Vmax2 = 0.004 nmol/min/pmol; Km1 = 7.1 µM; Vmax1 = 0.0001 nmol/min/pmol; AUC unchanged when with ketoconazole; AUC decreased 30% when with carbamazepine CYP2C8 Km = 79.1 µM; Vmax = 0.001 nmol/min/pmol; Unlikely P-gp, BCRP Contradictory: Ombitasvir was not a substrate of P-gp or BCRP mediated efflux in vitro, but mice lacking these transporters had increased exposure levels AUC unchanged when with cyclosporine; Cmax decreased by 23% when with atazanavir CYP2C8 CYP2C8 inhibitor quercetin inhibited in vitro metabolism in human liver microsomes by 60% Confirmed (AUC increased 1025% by gemfibrozil) CYP3A4 CYP3A inhibitor ketoconazole inhibited in vitro metabolism in human liver microsomes by 30% Confirmed (AUC increased 42% by ketoconazole; decreased 70% by carbamazepine P-gp Inhibited by LY335979 and cyclosporin A in vitro Confirmed C (AUC decreased 21% by OATP1B1 inhibitor atazanavir and 30% by inhibitor cyclosporin) BCRP Inhibited by BCRP inhibitor K0143 M1 BCRP Inhibited by BCRP inhibitor administered administered administered administered administered administered
M13-300 Effect of food on dasabuvir optimised tablets Ascending Single dose M12-351 Comparison of 3 single doses of paritaprevir SDD Formulation M11-032 Single ascending doses of dasabuvir Multi-dose M10-861 Multiple-ascending doses of paritaprevir M10-687 Multi-dose PKs of dasabuvir M12-187 Multi-dose PKs of ombitasvir and paritaprevir/ritonavir M11-603 PKs of dasabuvir plus paritaprevir/ ritonavir ADME M10-789 ADME of [14C] paritaprevir/ritonavir M12-186 ADME of [14C]ombitasvir PK in special popn Target population HCV Genotype 1 infected subjects M10-351 Antiviral activity, and PKs of single and multiple doses (2 Days) of dasabuvir M11-602 PKs, and antiviral activity of multi-dose paritaprevir/ ritonavir, dasabuvir, or ABT-072 each administered alone Hepatic impairment M12-215 PKs of a single dose of co-administered ombitasvir, dasabuvir, and paritaprevir/ ritonavir impairment M12-193 PKs of a single dose of co-administered ombitasvir, dasabuvir, and paritaprevir/ ritonavir Other special pop’n M12-221 PKs of multi-dose of ombitasvir and paritaprevir/ ritonavir in Han Chinese, Japanese, and Caucasians M12-688 PKs of a single dose of paritaprevir/ ritonavir in Han Chinese, Japanese and Caucasians M12-181 PKs of ombitasvir in Han Chinese, Japanese, and Caucasians M13-505 PKs of the co-formulated paritaprevir/ ritonavir /ombitasvir in Han Chinese and Japanese
Table 29: Pivotal Phase III trials76 Design of arms, treatment duration Placebo controlled, no cirrhosis M11-646 Multicentre, double blind genotype 1 (a and b) Treatment naïve without cirrhosis 631 Viekira Pak+RBV (12 Placebo 72 M13-098 Multicentre, double genotype 1 (a and b) Treatment without cirrhosis 394 Viekira Pak+RBV (12 weeks) Placebo 72 Viekira Pak-RBV versus VIEKIRA-Pak, no cirrhosis PEARL-II M13-389 Multicentre, open label genotype 1b, Treatment without cirrhosis 186 Viekira Pak+RBV ( 12 weeks) Viekira Pak (12 60 PEARL-III M13-961 Multicentre, double blind genotype 1b, Treatment naïve without cirrhosis 419 Viekira Pak+RBV ( 12 Viekira Pak (12 60 PEARL-IV M14-002 Multicentre, double genotype 1a Treatment naïve without cirrhosis 305 Viekira Pak+RBV ( 12 weeks) Viekira Pak (12 weeks) 60 Viekira Pak-RBV, cirrhosis randomised randomised ,