Comparative bioavailability Fifteen Bioavailability studies are listed in the dossier. Fourteen of these relate to the Viekira Pak components and have been reviewed in the separate parallel evaluation for Viekira Pak. The remaining study (Study M14-356) is a comparative bioavailability study between the proposed ribavirin 600 mg tablets and 3 x 200 mg Copegus ribavirin tablets. The study demonstrated bioequivalent of the two treatments because the 90% confidence intervals for Cmax and AUC0-t ratios fell within the normal bioequivalence range (0.80 to 1.25). A justification for not providing biostudies for the 200 mg and 400 mg tablets was provided and this is considered acceptable with respect to CMC aspects. Quality summary and conclusions Registration of the proposed Viekira Pak-RBV combination therapy composite pack, consisting of the following components: a new fixed-dose combination film coated tablet comprising of 75 mg paritaprevir, 50 mg ritonavir and 12.5 mg ombitasvir, and dasabuvir (as sodium salt) 250 mg film coated tablets, ribavirin 200 mg, 400 mg and/or 600 mg film coated tablets is recommended with respect to quality and biopharmaceutic aspects. All issues raised during the initial evaluation of this application have now been satisfactorily resolved apart from some minor PI and labelling revisions. As no significant pharmaceutical chemistry issues were identified, the CMC aspects of the submission were not referred to the Pharmaceutical Subcommittee of the ACPM, in keeping with recent branch policy. III. Nonclinical findings Introduction The nonclinical evaluation of this submission has been performed in four parts the first three for each of the new chemical entities and the third for the combination product; Paritaprevir Ombitasvir Dasabuvir Fixed dose combination Each of these will be presented separately below.
Relative exposure - ombitasvir Relative exposure ratios are calculated based on clinical AUC0-24h values that were determined from a study in healthy volunteers (Study No. R&D/14/0050). Exposures attained in the pivotal toxicity studies were adequate multiples of clinical plasma levels. Table 5: Relative exposure to ombitasvir in repeat-dose toxicity and carcinogenicity studies - ombitasvir Species Study duration Sex Dose h ratio# Mouse [Tg(Hras)] Study No. R&D/12/574 26 week male 2.5 2.67 2 10 10.7 7.5 150 36.6 26 female 5 2.98 2.1 20 12.4 8.7 150 37 26 Mouse [CD-1] Study No. R&D/11/561 6 month [Pivotal toxicity] Sampling day: 182 male 5 3.57 2.5 20 10.5 7.4 200 40.8 29 female 10 3.38 2.4 40 17.9 12.6 200 32.1 23 Rat [SD] Study No. R&D/10/1472 3 month [Pivotal toxicity] Sampling day: 91 male/ female 10 10.7/9.2 7.5/6.5 30 14.4/18 300 16/25 Dog [Beagle] Study No. R&D/10/1371 6 [Pivotal toxicity] Sampling day: 189 male/ female 4 8.5/6 6/4.2 20 54/41.5 38/29 100 90/77 Study R&D/14/0500 Steady state – 25 mg/day 1.42 –
Km1 = 7.1 µM; Vmax1 = 0.0001 nmol/min/pmol; 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 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 K0143 Not tested Km = 1.30 µM Km = 1.71 µM † Data taken from reports RD13893 and RD13811 a: Studies in KO mice indicate that OATP transporters affect the distribution between liver and plasma. Table 14: paritaprevir/ombitasvir/dasabuvir as perpetrators for Enzyme or Nonclinical Findings Clinical Relevance administered administered
IC50 = 0.5 µM Clinical study showed increased rosuvastatin & pravastatin exposure with the 3DAA regimen, but individual contribution unknown IC50 = 0.6 µM OCT1 IC50 = 2.5 µM Ritonavir (and other compounds in the 3DAA regimen) have low potential for clinically relevant interactions with renal transporters; Clinically, tenofovir exposure was similar following co-administration with the 2DAA and 3DAA regimens OAT1 IC50 = 14 µM OAT3 IC50 = 8.1 µM MATE1 IC50 = 3.3 µM MATE2K IC50 = 90 µM BSEP IC50 = 0.1 µM UGT1A1 IC50 = 2.1 µM Possible; (clinical study showed 34% decrease in raltegravir exposure with the 3DAA regimen, but individual contribution unknown) CYP2C9 IC50 = 9 µM Unlikely 1.08) 60 Confirmed clinically (lack of interaction with warfarin) CYP2C8 IC50 = 17 µM Unlikely CYP2C19 IC50 = 18 µM Unlikely; (clinical study showed 38% reduction in omeprazole AUC) UGT1A1 IC50 = 0.92 µM Possible; (clinical study showed 34% decrease in raltegravir exposure with the 3DAA regimen, but individual contribution unknown) IC50 = 0.9 µM Unlikely (R-value = 1.06) IC50 = 6.6 µM Unlikely (R-value = 1.01) P-gp IC50 = 16.7 µM Possible, but not confirmed clinically (no increase in digoxin exposure when as part of 3DAA regimen) BCRP IC50 = 15.6 µM administered
PEARL-II M13-389 open GT1b, Treatment without cirrhosis 186 Viekira Pak+RBV ( 12 weeks) Viekira Pak (12 weeks) 60 weeks PEARL-III M13-961 double blind GT1b, Treatment without cirrhosis 419 Viekira Pak+RBV ( 12 weeks) Viekira Pak (12 weeks) 60 weeks PEARL-IV M14-002 double blind GT1a Treatment naïve without cirrhosis 305 Viekira Pak+RBV ( 12 weeks) Viekira Pak (12 weeks) 60 weeks Viekira Pak-RBV, cirrhosis M13-099 open label GT1 (a and b) Treatment and treatment naïve with cirrhosis 380 Viekira Pak+RBV ( 12 weeks) Viekira Pak+RBV (24 72 weeks M11-646, SAPPHIRE-I Genotype 1, treatment naïve. This was a Phase III, multicentre, randomised, double blind, placebo controlled safety and efficacy study of paritaprevir/ritonavir/ ombitasvir and dasabuvir co-administered with ribavirin (3DAA + RBV) in treatment naïve non-cirrhotic adults with genotype 1 chronic HCV infection. It was conducted at 79 centres in 13 countries. The primary efficacy objective was to show the non-inferiority in SVR12 rates after 12 weeks of treatment with 3DAA + RBV, compared with the historical SVR rate for telaprevir plus pegIFN/RBV. Approximately 600 patients were randomised to one of two arms in a 3:1 ratio to receive 3DAA + RBV for 12 weeks (Group A), or placebo 3DAA + RBV for 12 weeks followed by 3DAA + RBV for 12 weeks (Group B). In the double blind treatment period, randomisation was stratified according to HCV subtype (1a and non-1a) and IL28B genotype (CC and The duration of the study was 72 weeks consisting of a double blind treatment period, an open label treatment period (for patients randomised to placebo) and a post dosing period. All patients who received active study drugs were followed for 48 weeks post TURQUOISE non-