Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
Pharmacotherapeutic group: Antivirals for systemic use; direct-acting antivirals
ATC code: J05AP53
Viekirax, when co-administered with dasabuvir, combines three direct-acting antiviral medicinal products with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle. Refer to the Summary of Product Characteristics of dasabuvir for its pharmacological properties.
Ritonavir is not active against HCV. Ritonavir is a CYP3A inhibitor that increases the systemic exposure of the CYP3A substrate paritaprevir.
Ombitasvir is an inhibitor of HCV NS5A which is essential for viral replication.
Paritaprevir is an inhibitor of HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication.
The EC50 of ombitasvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays was 14.1 and 5 pM, respectively. The activity of ombitasvir was attenuated 11- to 13-fold in the presence of 40% human plasma. The mean EC50 of ombitasvir against replicons containing NS5A from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.66 pM (range 0.35 to 0.88 pM; n=11) and 1.0 pM (range 0.74 to 1.5 pM; n=11), respectively. Ombitasvir has EC50 values of 12, 4.3, 19, 1.7, 3.2, and 366 pM against replicon cell lines constructed with NS5A from single isolates representing genotypes 2a, 2b, 3a, 4a, 5a, and 6a, respectively.
The EC50 of paritaprevir against genotype 1a-H77 and 1b-Con1 strains in the HCV replicon cell culture assay was 1.0 and 0.21 nM, respectively. The activity of paritaprevir was attenuated 24 to 27 -fold in the presence of 40% human plasma. The mean EC50 of paritaprevir against replicons containing NS3 from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.86 nM (range 0.43 to 1.87 nM; n=11) and 0.06 nM (range 0.03 to 0.09 nM; n=9), respectively. Paritaprevir had an EC50 value of 5.3 nM against the 2a-JFH-1 replicon cell line, and EC50 values of 19, 0.09, and 0.68 nM against replicon cell lines containing NS3 from a single isolate each of genotype 3a, 4a, and 6a, respectively
Ritonavir did not exhibit a direct antiviral effect on the replication of HCV subgenomic replicons, and the presence of ritonavir did not affect the in vitro antiviral activity of paritaprevir.
Resistance to paritaprevir and ombitasvir conferred by variants in NS3 and NS5A respectively, selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterised in the appropriate genotype 1a or 1b replicons.
In genotype 1a, substitutions F43L, R155K, A156T, and D168A/F/H/V/Y in HCV NS3 reduced susceptibility to paritaprevir. In the genotype 1a replicon, the activity of paritaprevir was reduced 20-, 37-, and 17-fold by the F43L, R155K and A156T substitutions, respectively. The activity of paritaprevir was reduced 96-fold by D168V, and 50- to 219-fold by each of the other D168 substitutions. The activity of paritaprevir in genotype 1a was not significantly affected (less than or equal to 3-fold) by single substitutions V36A/M, V55I, Y56H, Q80K or E357K. Double variants including combinations of V36LM, F43L, Y56H, Q80K or E357K with R155K or with a D168 substitution reduced the activity of paritaprevir by an additional 2 to 3-fold relative to the single R155K or D168 substitution. In the genotype 1b replicon, the activity of paritaprevir was reduced 76- and 159-and 337- fold by D168A, D168H, D168V, and D168Y respectively. Y56H alone could not be evaluated due to poor replication capacity, however, the combination of Y56H and D168A/V/Y reduced the activity of paritaprevir by 700- to 4118- fold.
In genotype 1a, substitutions M28T/V, Q30E/R, L31V, H58D, Y93C/H/N, and M28V + Q30R in HCV NS5A reduced susceptibility to ombitasvir. In the genotype 1a replicon, the activity of ombitasvir was reduced by 896-, 58- and 243-fold against the M28T/V and H58D substitutions, respectively, and 1326-, 800-, 155-foldand 1675- to 66740- fold by the Q30E/R, L31V and Y93C/H/N substitutions, respectively. Y93H, Y93N or M28V in combination with Q30R reduced the activity of ombitasvir by more than 42,802-fold. In genotype 1b, substitutions L28T, L31F/V, as well as Y93H alone or in combination with L28M, R30Q, L31F/M/V or P58S in HCV NS5A reduced susceptibility to ombitasvir. In the genotype 1b replicon, the activity of ombitasvir was reduced by less than 10-fold by variants at amino acid positions 30 and 31. The activity of ombitasvir was reduced by 661-, 77-, 284- and 142-fold against the genotype 1b substitutions L28T, Y93H, R30Q in combination with Y93H, and L31M in combination with Y93H, respectively. All other double substitutions of Y93H in combination with substitutions at positions 28, 31, or 58 reduced the activity of ombitasvir by more than 400-fold.
In genotype 4a, resistance to paritaprevir or ombitasvir by variants in NS3 or NS5A, respectively, selected in cell culture were phenotypically characterised. Substitutions R155C, A156T/V, and D168H/V in HCV NS3 reduced susceptibility to paritaprevir by 40- to 323-fold. Substitution L28V in HCV NS5A reduced the susceptibility to ombitasvir by 21-fold.
A pooled analysis of subjects with genotype 1 HCV infection, who were treated with ombitasvir, paritaprevir, and dasabuvir (a non-nucleotide NS5B inhibitor) with or without ribavirin in the Phase 2b and 3 clinical trials was conducted to explore the association between baseline NS3/4A, NS5A or NS5B substitutions/polymorphisms and treatment outcome in recommended regimens.
In the greater than 500 genotype 1a baseline samples in this analysis, the most frequently observed resistance-associated variants were M28V (7.4%) in NS5A and S556G (2.9%) in NS5B. Q80K, although a highly prevalent polymorphism in NS3 (41.2% of samples), confers minimal resistance to paritaprevir.
Resistance-associated variants at amino acid positions R155 and D168 in NS3 were rarely observed (less than 1%) at baseline. In the greater than 200 genotype 1b baseline samples in this analysis, the most frequently observed resistance-associated variants observed were Y93H (7.5%) in NS5A, and C316N (17.0%) and S556G (15%) in NS5B. Given the low virologic failure rates observed with recommended treatment regimens for HCV genotype 1a- and 1b-infected subjects, the presence of baseline variants appears to have little impact on the likelihood of achieving SVR.
Of the 2,510 HCV genotype 1 infected subjects who were treated with regimens containing ombitasvir, paritaprevir, and dasabuvir with or without ribavirin (for 8, 12, or 24 weeks) in Phase 2b and 3 clinical trials, a total of 74 subjects (3%) experienced virologic failure (primarily post-treatment relapse). Treatment-emergent variants and their prevalence in these virologic failure populations are shown in Table 5. In the 67 genotype 1a infected subjects, NS3 variants were observed in 50 subjects, NS5A variants were observed in 46 subjects, NS5B variants were observed in 37 subjects, and treatmentemergent variants were seen in all 3 drug targets in 30 subjects. In the 7 genotype 1b infected subjects, treatment-emergent variants were observed in NS3 in 4 subjects, in NS5A in 2 subjects, and in both NS3 and NS5A in 1 subject. No genotype 1b infected subjects had treatment-emergent variants in all 3 drug targets.
Table 5. Treatment-emergent amino acid substitutions in the pooled analysis of Viekirax and dasabuvir with and without RBV regimens in Phase 2b and Phase 3 clinical trials (N=2510):
| Target | Emergent amino acid substitutionsa | Genotype 1a N=67b % (n) | Genotype 1b N=7 % (n) |
|---|---|---|---|
| NS3 | V55Ic | 6 (4) | -- |
| Y56Hc | 9 (6) | 42.9 (3)d | |
| I132Vc | 6 (4) | -- | |
| R155K | 13.4 (9) | -- | |
| D168A | 6 (4) | -- | |
| D168V | 50.7 (34) | 42.9 (3)d | |
| D168Y | 7.5 (5) | -- | |
| V36Ac, V36Mc, F43Lc, D168H, E357Kc | <5% | -- | |
| NS5A | M28T | 20.9 (14) | -- |
| M28Ve | 9 (6) | -- | |
| Q30Re | 40.3 (27) | -- | |
| Y93H | 28.6 (2) | ||
| H58D, H58P, Y93N | <5% | -- | |
| NS5B | A553T | 6.1 (4) | -- |
| S556G | 33.3 (22) | -- | |
| C316Y, M414T, G554S, S556R, G558R, D559G, D559N, Y561H | <5% | -- |
a Observed in at least 2 subjects of the same subtype.
b N=66 for the NS5B target.
c Substitutions were observed in combination with other emergent substitutions at NS3 position R155 or D168.
d Observed in combination in genotype 1b-infected subjects.
e Observed in combination in 6% (4/67) of the subjects.
Note: The following variants were selected in cell culture but were not treatment-emergent: NS3 variants A156T in genotype 1a, and R155Q and D168H in genotype 1b; NS5A variants Y93C/H in genotype 1a, and L31F/V or Y93H in combination with L28M, L31F/V or P58S in genotype 1b; and NS5B variants Y448H in genotype 1a, and M414T and Y448H in genotype 1b.
The persistence of paritaprevir, ombitasvir, and dasabuvir resistance-associated amino acid substitutions in NS3, NS5A, and NS5B, respectively, was assessed in genotype 1a-infected subjects in Phase 2b trials. Paritaprevir treatment-emergent variants V36A/M, R155K or D168V were observed in NS3 in 47 subjects. Ombitasvir treatment-emergent variants M28T, M28V or Q30R in NS5A were observed in 32 subjects. Dasabuvir treatment-emergent variants M414T, G554S, S556G, G558R or D559G/N in NS5B were observed in 34 subjects.
NS3 variants V36A/M and R155K and NS5B variants M414T and S556G remained detectable at posttreatment Week 48, whereas NS3 variant D168V and all other NS5B variants were not observed at posttreatment Week 48. All treatment-emergent variants in NS5A remained detectable at post-treatment Week 48. Due to high SVR rates in genotype 1b, trends in persistence of treatment-emergent variants in this genotype could not be established.
The lack of detection of virus containing a resistance-associated substitution does not indicate that the resistant virus is no longer present at clinically significant levels. The long-term clinical impact of the emergence or persistence of virus containing Viekirax- and dasabuvir-resistance-associated substitutions on future treatment is unknown. Cross-resistance Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B inhibitors by class. The impact of prior ombitasvir, paritaprevir or dasabuvir treatment experience on the efficacy of other NS5A inhibitors, NS3/4A protease inhibitors, or NS5B inhibitors has not been studied.
The efficacy and safety of Viekirax in combination with dasabuvir with and without ribavirin was evaluated in eight Phase 3 clinical trials, including two trials exclusively in subjects with cirrhosis (ChildPugh A), in over 2,360 subjects with genotype 1 chronic hepatitis C infection as summarised in Table 6.
Table 6. Phase 3 global multicentre studies conducted with Viekirax and dasabuvir with or without ribavirin (RBV):
| Trial | Number of subjects treated | HCV genotype (GT) | Summary of study design |
|---|---|---|---|
| Treatment-naïve, without cirrhosis | |||
| SAPPHIRE I | 631 | GT1 | Arm A: Viekirax and dasabuvir + RBV Arm B: Placebo |
| PEARL III | 419 | GT1b | Arm A: Viekirax and dasabuvir + RBV Arm B: Viekirax and dasabuvir |
| PEARL IV | 305 | GT1a | Arm A: Viekirax and dasabuvir + RBV Arm B: Viekirax and dasabuvir |
| GARNET (open-label) | 166 | GT1b | Viekirax and dasabuvir (8 weeks) |
| Peginterferon+ribavirin experienced, without cirrhosis | |||
| SAPPHIRE II | 394 | GT1 | Arm A: Viekirax and dasabuvir + RBV Arm B: Placebo |
| PEARL II (open-label) | 179 | GT1b | Arm A: Viekirax and dasabuvir + RBV Arm B: Viekirax and dasabuvir |
| Treatment-naïve and peginterferon+ribavirin -experienced, with compensated cirrhosis | |||
| TURQUOISE II (open-label) | 380 | GT1 | Arm A: Viekirax and dasabuvir + RBV (12 weeks) Arm B: Viekirax and dasabuvir + RBV (24 weeks) |
| TURQUOISE III (open-label) | 60 | GT1b | Viekirax and dasabuvir (12 weeks) |
In all eight trials, the Viekirax dose was 25 mg/150 mg/100 mg once daily and the dasabuvir dose was 250 mg twice daily. For subjects who received ribavirin, the ribavirin dose was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg.
Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate in the Phase 3 studies and was defined as unquantifiable or undetectable HCV RNA 12 weeks after the end of treatment (SVR12). Treatment duration was fixed in each trial and was not guided by subjects' HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System (except GARNET which used COBAS AmpliPrep/COBAS TaqMan HCV Test v2.0). The High Pure system assay had a lower limit of quantification (LLOQ) of 25 IU per mL and the AmpliPrep assay had a LLOQ of 15 IU per mL.
Design: randomised, global multicentre, double-blind, placebo-controlled
Treatment: Viekirax and dasabuvir with weight-based ribavirin for 12 weeks
Treated subjects (N=631) had a median age of 52 years (range: 18 to 70); 54.5% were male; 5.4% were Black; 15.2% had a history of depression or bipolar disorder; 79.1% had baseline HCV RNA levels of at least 800,000 IU/mL; 15.4% had portal fibrosis (F2) and 8.7% had bridging fibrosis (F3); 67.7% had HCV genotype 1a infection; 32.3% had HCV genotype 1b infection.
Table 7. SVR12 for genotype 1-infected treatment-naïve subjects in SAPPHIRE-I:
| Treatment outcome | Viekirax and dasabuvir with RBV for 12 weeks | ||
|---|---|---|---|
| n/N | % | 95% CI | |
| Overall SVR12 | 456/473 | 96.4 | 94.7, 98.1 |
| HCV genotype 1a | 308/322 | 95.7 | 93.4, 97.9 |
| HCV genotype 1b | 148/151 | 98.0 | 95.8, 100.0 |
| Outcome for subjects without SVR12 | |||
| On-treatment VFa | 1/473 | 0.2 | |
| Relapse | 7/463 | 1.5 | |
| Otherb | 9/473 | 1.9 | |
a Confirmed HCV ≥25 IU/mL after HCV RNA <25 IU/mL during treatment, confirmed 1 log10 IU/mL increase in HCV RNA from nadir, or HCV RNA persistently ≥25 IU/mL with at least 6 weeks of treatment.
b Other includes early drug discontinuation not due to virologic failure missing HCV RNA values in the SVR12 window.
No subjects with HCV genotype 1b infection experienced on-treatment virologic failure and one subject with HCV genotype 1b infection experienced relapse.
Design: randomised, global multicentre, double-blind, regimen-controlled
Treatment: Viekirax and dasabuvir without ribavirin or with weight-based ribavirin for 12 weeks
Treated subjects (N=419) had a median age of 50 years (range: 19 to 70), 45.8% were male; 4.8% were Black; 9.3% had a history of depression or bipolar disorder; 73.3% had baseline HCV RNA of at least 800,000 IU/mL; 20.3% had portal fibrosis (F2) and 10.0% had bridging fibrosis (F3).
Table 8. SVR12 for genotype 1b-infected treatment-naïve subjects in PEARL III:
| Treatment outcome | Viekirax and dasabuvir for 12 weeks | |||||
|---|---|---|---|---|---|---|
| With RBV | Without RBV | |||||
| n/N | % | 95% CI | n/N | % | 95% CI | |
| Overall SVR12 | 209/210 | 99.5 | 98.6, 100.0 | 209/209 | 100 | 98.2, 100.0 |
| Outcome for subjects without SVR12 | ||||||
| On-treatment VF | 1/210 | 0.5 | 0/209 | 0 | ||
| Relapse | 0/210 | 0 | 0/209 | 0 | ||
| Other | 0/210 | 0 | 0/209 | 0 | ||
Design: randomised, global multicentre, double-blind, regimen-controlled
Treatment: Viekirax and dasabuvir without ribavirin or with weight-based ribavirin for 12 weeks
Treated subjects (N=305) had a median age of 54 years (range: 19 to 70); 65.2% were male; 11.8% were Black; 20.7% had a history of depression or bipolar disorder; 86.6% had baseline HCV RNA levels of at least 800,000 IU/mL; 18.4% had portal fibrosis (F2) and 17.7% had bridging fibrosis (F3).
Table 9. SVR12 for genotype 1a-infected treatment-naïve subjects in PEARL IV:
| Treatment outcome | Viekirax and dasabuvir for 12 weeks | |||||
|---|---|---|---|---|---|---|
| With RBV | Without RBV | |||||
| n/N | % | 95% CI | n/N | % | 95% CI | |
| Overall SVR12 | 97/100 | 97.0 | 93.7, 100.0 | 185/205 | 90.2 | 86.2, 94.3 |
| Outcome for subjects without SVR12 | ||||||
| On-treatment VF | 1/100 | 1.0 | 6/205 | 2.9 | ||
| Relapse | 1/98 | 1.0 | 10/194 | 5.2 | ||
| Other | 1/100 | 1.0 | 4/205 | 2.0 | ||
Design: open-label, single-arm, global multicentre
Treatment: Viekirax and dasabuvir for 8 weeks
Treated subjects (N=166) had a median age of 53 years (range: 22 to 82); 56.6% were female; 3.0% were Asian; 0.6% were Black; 7.2% had baseline HCV RNA levels of at least 6,000,000 IU per mL; 9% had advanced fibrosis (F3) and 98.2% had HCV genotype 1b infection (one subject each had genotype 1a, 1d, and 6 infection).
Table 10. SVR12 for Genotype 1b-infected treatment-naïve subjects without cirrhosis:
| Viekirax and dasabuvir for 8 weeks n/N (%) | |
|---|---|
| SVR12 | 160/163 (98.2) |
| 95% CIa | 96.1, 100.0 |
| F0-F1 | 138/139 (99.3)b |
| F2 | 9/9 (100) |
| F3 | 13/15 (86.7)c |
a Calculated using the normal approximation to the binomial distribution
b 1 patient discontinued due to non-compliance
c Relapse in 2/15 patients (confirmed HCV RNA ≥15 IU/mL post-treatment before or during SVR12 window among subjects with HCV RNA <15 IU/mL at last observation with at least 51 days of treatment).
Design: randomised, global multicentre, double-blind, placebo-controlled
Treatment: Viekirax and dasabuvir with weight-based ribavirin for 12 weeks
Treated subjects (N=394) had a median age of 54 years (range: 19 to 71); 49.0% were prior pegIFN/RBV null responders; 21.8/% were prior pegIFN/RBV partial responders, and 29.2% were prior pegIFN/RBV relapsers; 57.6% were male; 8.1% were Black; 20.6% had a history of depression or bipolar disorder; 87.1% had baseline HCV RNA levels of at least 800,000 IU per mL; 17.8% had portal fibrosis (F2) and 14.5% had bridging fibrosis (F3); 58.4% had HCV genotype 1a infection; 41.4% had HCV genotype 1b infection.
Table 11. SVR12 for genotype 1-infected peginterferon+ribavirin-experienced subjects in SAPPHIRE-II:
| Treatment outcome | Viekirax and dasabuvir with RBV for 12 weeks | ||
|---|---|---|---|
| n/N | % | 95% CI | |
| Overall SVR12 | 286/297 | 96.3 | 94.1, 98.4 |
| HCV genotype 1a | 166/173 | 96.0 | 93.0, 98.9 |
| Prior pegIFN/RBV null responder | 83/87 | 95.4 | 91.0, 99.8 |
| Prior pegIFN/RBV partial responder | 36/36 | 100 | 100.0, 100.0 |
| Prior pegIFN/RBV relapser | 47/50 | 94.0 | 87.4, 100.0 |
| HCV genotype 1b | 119/123 | 96.7 | 93.6, 99.9 |
| Prior pegIFN/RBV null responder | 56/59 | 94.9 | 89.3, 100.0 |
| Prior pegIFN/RBV partial responder | 28/28 | 100 | 100.0, 100.0 |
| Prior pegIFN/RBV relapser | 35/36 | 97.2 | 91.9, 100.0 |
| Outcome for subjects without SVR12 | |||
| On-treatment VF | 0/297 | 0 | |
| Relapse | 7/293 | 2.4 | |
| Other | 4/297 | 1.3 | |
No subjects with HCV genotype 1b infection experienced on-treatment virologic failure and 2 subjects with HCV genotype 1b infection experienced relapse.
Design: randomised, global multicentre, open-label
Treatment: Viekirax and dasabuvir without ribavirin or with weight-based ribavirin for 12 weeks
Treated subjects (N=179) had a median age of 57 years (range: 26 to 70); 35.2% were prior pegIFN/RBV null responders; 28.5% were prior pegIFN/RBV partial responders, and 36.3% were prior pegIFN/RBV relapsers; 54.2% were male; 3.9% were Black; 12.8% had a history of depression or bipolar disorder; 87.7% had baseline HCV RNA levels of at least 800,000 IU/mL; 17.9% had portal fibrosis (F2) and 14.0% had bridging fibrosis (F3).
Table 12. SVR12 for genotype 1b-infected peginterferon+ribavirin-experienced subjects in PEARL II:
| Treatment outcome | Viekirax and dasabuvir for 12 weeks | |||||
|---|---|---|---|---|---|---|
| With RBV | Without RBV | |||||
| n/N | % | 95% CI | n/N | % | 95% CI | |
| Overall SVR12 | 86/88 | 97.7 | 94.6, 100.0 | 91/91 | 100 | 95.9, 100.0 |
| Prior pegIFN/RBV null responder | 30/31 | 96.8 | 90.6, 100.0 | 32/32 | 100 | 89.3, 100.0 |
| Prior pegIFN/RBV partial responder | 24/25 | 96.0 | 88.3, 100.0 | 26/26 | 100 | 87.1, 100.0 |
| Prior pegIFN/RBV relapser | 32/32 | 100 | 89.3, 100.0 | 33/33 | 100 | 89.6, 100.0 |
| Outcome for subjects without SVR12 | ||||||
| On-treatment VF | 0/88 | 0 | 0/91 | 0 | ||
| Relapse | 0/88 | 0 | 0/91 | 0 | ||
| Other | 2/88 | 2.3 | 0/91 | 0 | ||
Design: randomised, global multicentre, open-label
Treatment: Viekirax and dasabuvir with weight-based ribavirin for 12 or 24 weeks
Treated subjects (N=380) had a median age of 58 years (range: 21 to 71); 42.1% were treatment-naïve, 36.1% were prior pegIFN/RBV null responders; 8.2% were prior pegIFN/RBV partial responders, 13.7% were prior pegIFN/RBV relapsers; 70.3% were male; 3.2% were Black; 14.7% had platelet counts of less than 90 × 109/L; 49.7% had albumin less than 40 g/L; 86.1% had baseline HCV RNA levels of at least 800,000 IU/mL; 24.7% had a history of depression or bipolar disorder; 68.7% had HCV genotype 1a infection, 31.3% had HCV genotype 1b infection.
Table 13. SVR12 for genotype 1-infected subjects with compensated cirrhosis who were treatmentnaïve or previously treated with pegIFN/RBV:
| Treatment outcome | Viekirax and dasabuvir with RBV | |||||
|---|---|---|---|---|---|---|
| 12 weeks | 24 weeks | |||||
| n/N | % | CIa | n/N | % | CIa | |
| Overall SVR12 | 191/208 | 91.8 | 87.6, 96.1 | 166/172 | 96.5 | 93.4, 99.6 |
| HCV genotype 1a | 124/140 | 88.6 | 83.3, 93.8 | 115/121 | 95.0 | 91.2, 98.9 |
| Treatment naïve | 59/64 | 92.2 | 53/56 | 94.6 | ||
| Prior pegIFN/RBV null responders | 40/50 | 80.0 | 39/42 | 92.9 | ||
| Prior pegIFN/RBV partial responders | 11/11 | 100 | 10/10 | 100 | ||
| Prior pegIFN/RBV Prior relapsers | 14/15 | 93.3 | 13/13 | 100 | ||
| HCV genotype 1b | 67/68 | 98.5 | 95.7, 100 | 51/51 | 100 | 93.0, 100 |
| Treatment naïve | 22/22 | 100 | 18/18 | 100 | ||
| Prior pegIFN/RBV null responders | 25/25 | 100 | 20/20 | 100 | ||
| Prior pegIFN/RBV partial responders | 6/7 | 85.7 | 3/3 | 100 | ||
| Prior pegIFN/RBV Prior relapsers | 14/14 | 100 | 10/10 | 100 | ||
| Outcome for subjects without SVR12 | ||||||
| On-treatment VF | 1/208 | 0.5 | 3/172 | 1.7 | ||
| Relapse | 12/203 | 5.9 | 1/164 | 0.6 | ||
| Other | 4/208 | 1.9 | 2/172 | 1.21 | ||
a 97.5% confidence intervals are used for the primary efficacy endpoints (overall SVR12 rate); 95% confidence intervals are used for additional efficacy endpoints (SVR12 rates in HCV genotype 1a and 1b-infected subjects).
Relapse rates in GT1a cirrhotic subjects by baseline laboratory values are presented in Table 14.
Table 14. TURQUOISE-II: Relapse Rates by Baseline Laboratory Values after 12 and 24 Weeks of Treatment in Subjects with Genotype 1a Infection and Compensated Cirrhosis:
| Viekirax and dasabuvir with RBV 12-week arm | Viekirax and dasabuvir with RBV 24-week arm | |
|---|---|---|
| Number of Responders at the End of Treatment | 135 | 113 |
| AFP* <20 ng/mL, platelets ≥90 × 109/L, AND albumin ≥35 g/L prior to treatment | ||
| Yes (for all three parameters listed above) | 1/87 (1%) | 0/68 (0%) |
| No (for any parameter listed above) | 10/48 (21%) | 1/45 (2%) |
* AFP= serum alpha fetoprotein
In subjects with all three favourable baseline laboratory values (AFP <20 ng/mL, platelets ≥90 × 109/L, and albumin ≥35 g/L), relapse rates were similar in subjects treated for 12 or 24 weeks.
Design: global multicentre, open-label
Treatment: Viekirax and dasabuvir without ribavirin for 12 weeks
60 patients were randomized and treated, and 60/60 (100%) achieved SVR12. Main characteristics are shown below.
Table 15. Main demographics in TURQUOISE-III:
| Characteristics | N=60 |
|---|---|
| Age, median (range) years | 60.5 (26-78) |
| Male gender, n (%) | 37 (61) |
| Prior HCV Treatment: | |
| naïve, n (%) | 27 (45) |
| Peg-IFN + RBV, n (%) | 33 (55) |
| Baseline albumin, median g/L | 40.0 |
| <35, n (%) | 10 (17) |
| ≥35, n (%) | 50 (83) |
| Baseline platelet count, median (x 109/L) | 132.0 |
| <90, n (%) | 13 (22) |
| ≥90, n (%) | 47 (78) |
Overall, 660 subjects in Phase 2 and 3 clinical trials had HCV RNA results for both the SVR12 and SVR24 time points. Among these subjects, the positive predictive value of SVR12 on SVR24 was 99.8%.
In Phase 3 clinical trials, 1075 subjects (including 181 with compensated cirrhosis) with genotype 1 HCV infection received the recommended regimen (see section 4.2). Table 16 shows SVR rates for these subjects.
In subjects who received the recommended regimen, 97% achieved SVR overall (among which 181 subjects with compensated cirrhosis achieved 97% SVR), while 0.5% experienced virologic breakthrough and 1.2% experienced post-treatment relapse.
Table 16. SVR12 rates for recommended treatment regimens by patient population:
| HCV Genotype 1b Viekirax and dasabuvir | HCV Genotype 1a Viekirax and dasabuvir with RBV | |||
|---|---|---|---|---|
| Without cirrhosis | With compensated cirrhosis | Without cirrhosis | With compensated cirrhosis | |
| Treatment duration | 12 weeks | 12 weeks | 12 weeks | 24 weeks |
| Treatment-naïve | 100% (210/210) | 100% (27/27) | 96% (403/420) | 95% (53/56) |
| pegIFN + RBV experienced | 100% (91/91) | 100% (33/33) | 96% (166/173) | 95% (62/65) |
| Prior relapse | 100% (33/33) | 100% (3/3) | 94% (47/50) | 100% (13/13) |
| Prior partial response | 100% (26/26) | 100% (5/5) | 100% (36/36) | 100% (10/10) |
| Prior null response | 100% (32/32) | 100% (7/7) | 95% (83/87) | 93% (39/42) |
| Other pegIFN/RBV failures | 0 | 100% (18/18)+ | 0 | 0 |
| TOTAL | 100% (301/301) | 100% (60/60) | 96% (569/593) | 95% (115/121) |
+ Other types of pegIFN/RBV failure include less well documented non-response, relapse/breakthrough or other pegIFN failure.
Viekirax without ribavirin and without dasabuvir was also evaluated in genotype 1b infected subjects in Phase 2 studies M13-393 (PEARL-I) and M12-536. PEARL I was conducted in the US and Europe, M12- 536 in Japan. The treatment-experienced subjects studied were primarily pegIFN/RBV null responders. The doses of ombitasvir, paritaprevir, ritonavir were 25 mg 150 mg, 100 mg once daily in PEARL-I, while the dose of paritaprevir was 100 mg or 150 mg in study M12-536. Treatment duration was 12 weeks for treatment naïve subjects, 12-24 weeks for treatment experienced subjects and 24 weeks for subjects with cirrhosis. Overall, 107 of 113 subjects without cirrhosis and 147 of 155 subjects with cirrhosis achieved SVR12 after 12-24 weeks of treatment.
Viekirax with ribavirin & without dasabuvir was evaluated for 12 weeks in genotype 1 treatment naive and treatment experienced non-cirrhotic subjects in a phase 2 study M11-652 (AVIATOR). The doses of paritaprevir were 100 mg and 200 mg and ombitasvir 25 mg. Ribavirin was dosed based on weight (1000 mg – 1200 mg per day). Overall, 72 of 79 treatment-naive subjects (45 of 52 GT1a and 27 of 27 GT1b) and 40 of 45 treatment-experienced subjects (21 of 26 GT1a and 19 of 19 GT1b) achieved SVR12 after 12 weeks of treatment.
In Phase 3 clinical trials, 91.5% of subjects did not require ribavirin dose adjustments during therapy. In the 8.5% of subjects who had ribavirin dose adjustments during therapy, the SVR rate (98.5%) was comparable to subjects who maintained their starting ribavirin dose throughout treatment.
Design: randomised, global multicentre, open-label
Treatment: Viekirax with or without dasabuvir coadminstered with or without weight-based ribavirin for 12 or 24 weeks
See section 4.2 for dosing recommendations in HCV/HIV-1 co-infected patients. HCV GT1- or 4-infected subjects with HIV-1 coinfection were on a stable HIV-1 antiretroviral therapy (ART) regimen that included ritonavir-boosted atazanavir, raltegravir, dolutegravir (Part 2 only), or darunavir (Part 1b and Part 2 GT4 only)-, co-administered with a backbone of tenofovir plus emtricitabine or lamivudine.
Part 1 of the study was a Phase 2 pilot cohort consisting of 2 parts, Part 1a (63 subjects) and Part 1b (22 subjects). Part 2 was a Phase 3 cohort consisting of 233 subjects.
In Part 1a, all subjects received Viekirax and dasabuvir with ribavirin for 12 or 24 weeks. Treated subjects (N=63) had a median age of 51 years (range: 31 to 69); 24% were Black; 19% had compensated cirrhosis; 67% were treatment-naïve; 33% had failed prior treatment with pegIFN/RBV; 89% had HCV genotype 1a infection.
In Part 1b, all subjects received Viekirax and dasabuvir with ribavirin for 12 weeks. Treated subjects (N=22) had a median age of 54 years (range: 34 to 68); 41% were Black; 14% had compensated cirrhosis; 86% were HCV treatment-naïve; 14% had failed prior treatment with pegIFN/RBV; 68% had HCV genotype 1a infection.
In Part 2, subjects with HCV GT1 received Viekirax and dasabuvir with or without ribavirin for 12 or 24 weeks. Subjects with HCV GT4 received Viekirax with ribavirin for 12 or 24 Weeks. Treated subjects (N=233) had a median age of 49 years (range: 26 to 69); 10% were Black; 12% had compensated cirrhosis; 66% were treatment-naïve; 32% had failed prior treatment with pegIFN/RBV; 2% had failed prior treatment with sofosbuvir.
Table 17 shows the primary efficacy analysis of SVR12 performed on subjects with HCV GT1/HIV-1 coinfection that received recommended regimen in Part 2 of the TURQUOISE-I study.
Table 17. Primary SVR12 Assessment for Part 2 Subjects with HCV GT1/HIV-1 co-infection in TURQUOISE-I:
| Endpoint | Viekirax and dasabuvir with/without ribavirin for 12 or 24 Weeks N=200a |
|---|---|
| SVR12, n/N () [95 CI] | 194/200 (97.0) [93.6, 98.6] |
| Outcome for subjects not achieving SVR12 | |
| On-treatment virologic failure | 1 |
| Post-treatment relapse | 1 |
| Otherb | 4 |
a Includes all HCV GT1 subjects in Part 2 excluding Arm G subjects that did not receive recommended regimen.
b Includes subjects who discontinued due to adverse event, loss to follow-up or subject withdrawal, and subjects with reinfection.
Efficacy analyses performed on other parts of the study demonstrated similarly high SVR12 rates. In Part 1a, SVR12 was achieved by 29/31 (93.5%) subjects on the 12-week arm (95% CI: 79.3%, 98.2%) and by 29/32 (90.6%) subjects on the 24-week arm (95% CI: 75.8% – 96.8%). There was 1 relapse in the 12- week arm and 1 on-treatment virologic failure in the 24-week arm. In Part 1b, SVR12 was achieved by 22/22 (100%) subjects (95% CI: 85.1%, 100%). In Part 2, SVR12 was achieved by 27/28 (96.4%) subjects with HCV GT4/HIV-1 coinfection (95% CI: 82.3%, 99.4%) with no virologic failures.
The SVR12 rates in HCV/HIV-1 co-infected subjects were thus consistent with SVR12 rates in the phase 3 trials of HCV mono-infected subjects.
Design: randomised, global multicentre, open-label
Treatment: Viekirax and dasabuvir for 12 or 24 weeks with or without ribavirin (investigator chosen dose) for GT1 and GT4 infection
In subjects with liver transplant, no cirrhosis and GT1 infection, patients were dosed with Viekirax and dasabuvir for 12-24 weeks, with and without RBV. Liver transplant subjects with cirrhosis were dosed with Viekirax and dasabuvir with RBV (GT1a for 24 weeks [n=4], GT1b for 12 weeks [n=2]). Subjects with renal transplant and no cirrhosis were dosed for 12 weeks (with RBV for GT1a [n=9], without RBV for GT1b [n=3]). Subjects with liver transplant and GT4 infection were dosed with Viekirax with RBV (non-cirrhotic for 12 weeks [n=2] and cirrhotic for 24 weeks [n=1]. The dose of ribavirin was left to the discretion of the investigator, with most subjects receiving 600 to 800 mg per day as a starting dose, and most subjects also receiving 600 to 800 mg per day at the end of treatment.
A total of 129 subjects were treated, 84 with GT1a, 41 with GT1b, 1 with GT1 other, 3 with GT4 infection. Overall, 61% had fibrosis stage F0-F1, 26% F2, 9% F3, and 4% F4. 61% had prior HCV treatment experience before transplant. For immunosuppressive medication, most subjects were taking tacrolimus (81%), with the remainder taking cyclosporine.
Among all GT1 subjects who were post liver transplant, 111/114 (97.4%) achieved SVR12; with 2 relapsing post treatment and 1 breakthrough on treatment. Among the GT1 subjects who were post renal transplant, 9/12 (75%) achieved SVR12; however, there were no virologic failures. All 3 (100%) subjects with GT4 infection who were post liver transplant achieved SVR12.
In a phase 2, multicentre, open-label, single arm study, 38 treatment-naïve or pegIFN/RBV treatment experienced, non-cirrhotic subjects with genotype 1 infection who were on stable doses of methadone (N=19) or buprenorphine +/- naloxone (N=19) received 12 weeks of Viekirax and dasabuvir with ribavirin. Treated subjects had a median age of 51 years (range: 26 to 64); 65.8% were male and 5.3% were Black. A majority (86.8%) had baseline HCV RNA levels of at least 800,000 IU/mL and a majority (84.2%) had genotype 1a infection; 15.8% had portal fibrosis (F2) and 5.3% had bridging fibrosis (F3); and 94.7% were naïve to prior HCV treatment.
Overall, 37 (97.4%) of 38 subjects achieved SVR12. No subjects experienced on-treatment virologic failure or relapse.
Design: multicentre, open-label
Treatment: Viekirax and dasabuvir with or without RBV for 12 or 24 weeks
Severe renal impairment or ESRD includes CKD Stage 4 defined as eGFR <30-15 mL/min/1.73 m² or CKD Stage 5 defined as <15 mL/min/1.73 m² or requiring haemodialysis. Treated subjects (N=68) had a median age of 58 years (range: 32-77 years); 83.8% were male; 58.8% were Black; 73.5% of subjects were infected with HCV GT1a; 75.0%% had Stage 5 CKD and 69.1% were on haemodialysis.
Sixty four of 68 (94.1%) subjects achieved SVR12. One subject experienced relapse at Post-Treatment Week 4, 2 subjects prematurely discontinued study drug and 1 subject had missing SVR12 data.
See also Section 4.8 for discussion of safety information for RUBY-I.
In another open-label phase 3b study evaluating 12 weeks of Viekirax with or without dasabuvir and without RBV in non-cirrhotic, treatment-naive GT1a and GT4 patients with CKD stage 4 or 5 (Ruby II), the SVR12 rate was 94.4% (17/18), with no subjects experiencing on-treatment virologic failure or relapse.
Design: randomised, global multicentre, open-label
Treatment: treatment naïve: Viekirax without ribavirin or with weight-based ribavirin for 12 weeks pegIFN + RBV experienced: Viekirax with weight-based ribavirin for 12 weeks
Subjects (N=135) had a median age of 51 years (range: 19 to 70); 63,7% were treatment-naïve, 17.0% were prior pegIFN/RBV null responders, 6.7% were prior pegIFN/RBV partial responders, 12.6% were prior pegIFN/RBV relapsers; 65.2%were male; 8.9% were Black, 69.6% had baseline HCV RNA levels at least 800,000 IU/mL; 6.7% had bridging fibrosis (F3).
Table 18. SVR12 for genotype 4-infected, subjects who were treatment-naïve or previously treated with pegIFN/RBV in PEARL I:
| Treatment outcome | Ombitasvir + paritaprevir + ritonavir* for 12 weeks | |||||
|---|---|---|---|---|---|---|
| Treatment-naïve With RBV | Treatment-naïve Without RBV | pegIFN + RBV- experienced With RBV | ||||
| n/N | % | n/N | % | n/N | % | |
| Overall SVR12 | 42/42 | 100% | 40/44 | 90.9% | 49/49 | 100% |
| Outcome for subjects without SVR12 | ||||||
| On-treatment VF | 0/42 | 0 | 1/44 | 2.3% | 0/49 | 0 |
| Relapse | 0/42 | 0 | 2/44 | 4.5% | 0/49 | 0 |
| Other | 0/42 | 0 | 1/44 | 2.3% | 0/49 | 0 |
* Ombitasvir tablets, paritaprevir tablets and ritonavir capsules administered separately.
Design: randomised, global multicentre, open-label
Treatment: Viekirax with weight-based ribavirin for 12 or 16 weeks
Subjects had a median age of 56 years (range: 32 to 81); 50% were treatment-naïve, 28% were prior pegIFN/RBV null responders; 10% were prior pegIFN/RBV partial responders, 13% were prior pegIFN/RBV relapsers; 70% were male; 17% were Black; 73% had baseline HCV RNA levels of at least 800,000 IU per mL; 17% had platelet counts of less than 90 × 109 per L; and 4% had albumin less than 3.5 mg per dL.
Table 19. SVR12 for HCV Genotype 4-Infected Subjects with Compensated Cirrhosis:
| Ombitasvir + Paritaprevir + Ritonavir with RBV | ||
|---|---|---|
| 12 Weeks | 16 Weeks | |
| SVR12 % (n/N) | 97% (57/59) | 98% (60/61) |
| Outcome for subjects without SVR12 | ||
| On-treatment virologic failure | 2 (1/59) | 0 (0/61) |
| Post-treatment relapse | 0 (0/57) | 0 (0/59) |
| Other | 2 (1/59) | 2 (1/61) |
The European Medicines Agency has deferred the obligation to submit the results of studies with Viekirax in one or more subsets of the paediatric populations in the treatment of chronic hepatitis C (see section 4.2 for information on paediatric use).
The pharmacokinetic properties of the combination of Viekirax with dasabuvir have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Table 20 shows mean Cmax and AUC of Viekirax 25 mg/150 mg/100 mg once daily with dasabuvir 250 mg twice daily following multiple doses with food in healthy volunteers.
Table 20. Geometric mean Cmax, AUC of multiple doses of Viekirax 150 mg/100 mg/25 mg once daily with dasabuvir 250 mg twice daily with food in healthy volunteers:
| Cmax (ng/ml) (% CV) | AUC (ng*hr/ml) (% CV) | |
|---|---|---|
| Ombitasvir | 127 (31) | 1420 (36) |
| Paritaprevir | 1470 (87) | 6990 (96) |
| Ritonavir | 1600 (40) | 9470 (41) |
Ombitasvir, paritaprevir and ritonavir were absorbed after oral administration with mean Tmax of approximately 4 to 5 hours. While ombitasvir exposures increased in a dose proportional manner, paritaprevir and ritonavir exposures increased in a more than dose proportional manner. Accumulation is minimal for ombitasvir and approximately 1.5- to 2-fold for ritonavir and paritaprevir. Pharmacokinetic steady state for the combination is achieved after approximately 12 days of dosing.
The absolute bioavailability of ombitasvir and paritaprevir was approximately 50% when administered with food as Viekirax.
In the presence of paritaprevir/ritonavir, dasabuvir exposures decreased by approximately 50% to 60% while ombitasvir exposures increased by 31-47%.
In the presence of ombitasvir, paritaprevir exposures were minimally affected (5% to 27% change) while dasabuvir exposures increase by approximately 30%.
In the presence of dasabuvir, paritaprevir exposures increased by 50% to 65% while there was no change in ombitasvir exposures.
Ombitasvir, paritaprevir and ritonavir should be administered with food. All clinical trials with ombitasvir, paritaprevir and ritonavir have been conducted following administration with food.
Food increased the exposure (AUC) of ombitasvir, paritaprevir and ritonavir by up to 82%, 211% and 49%, respectively relative to the fasting state. The increase in exposure was similar regardless of meal type (e.g., high-fat versus moderate-fat) or calorie content (approximately 600 Kcal versus approximately 1000 Kcal). To maximise absorption, Viekirax should be taken with food without regard to fat or calorie content.
Ombitasvir, paritaprevir and ritonavir are highly bound to plasma proteins. Plasma protein binding is not meaningfully altered in subjects with renal or hepatic impairment. The blood to plasma concentration ratios in humans ranged from 0.6 to 0.8 indicating that ombitasvir and paritaprevir were preferentially distributed in the plasma compartment of whole blood. Ombitasvir was approximately 99.9% bound to human plasma proteins. Paritaprevir was approximately 97-98.6% bound to human plasma proteins. Ritonavir was greater than 99% bound to human plasma proteins.
In vitro data indicate that paritaprevir is a substrate for the human hepatic uptake transporters, OATP1B1 and OATP1B3.
Ombitasvir is metabolised via amide hydrolysis followed by oxidative metabolism. Following a 25 mg single dose of 14C-ombitasvir given alone, unchanged parent drug accounted for 8.9% of total radioactivity in human plasma; a total of 13 metabolites were identified in human plasma. These metabolites are not expected to have antiviral activity or off-target pharmacologic activity.
Paritaprevir is metabolised predominantly by CYP3A4 and to a lesser extent CYP3A5. Following administration of a single 200 mg/100 mg oral dose of 14C paritaprevir /ritonavir to humans, the parent drug was the major circulating component, accounting for approximately 90% of the plasma radioactivity. At least 5 minor metabolites of paritaprevir have been identified in circulation that accounted for approximately 10% of plasma radioactivity. These metabolites are not expected to have antiviral activity.
Ritonavir is predominantly metabolised by CYP3A and to a lesser extent, by CYP2D6. Nearly the entire plasma radioactivity after a single 600 mg dose of 14C-ritonavir oral solution in humans was attributed to unchanged ritonavir.
Following dosing of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, mean plasma half-life of ombitasvir was approximately 21 to 25 hours. Following a single 25 mg dose of 14C- ombitasvir approximately 90% of the radioactivity was recovered in faeces and 2% in urine. Unchanged parent drug accounted for 88% of total radioactivity recovered in faeces, indicating that biliary excretion is a major elimination pathway for ombitasvir.
Following dosing of ombitasvir/paritaprevir /ritonavir with or without dasabuvir, mean plasma half-life of paritaprevir was approximately 5.5 hours. Following a 200 mg 14C -paritaprevir dose with 100 mg ritonavir, approximately 88% of the radioactivity was recovered in faeces with limited radioactivity (8.8%) in urine. Metabolism as well as biliary excretion of parent drug contribute to the elimination of paritaprevir.
Following dosing of ombitasvir/paritaprevir /ritonavir, mean plasma half-life of ritonavir was approximately 4 hours. Following a 600 mg dose of 14C-ritonavir oral solution, 86.4% of the radioactivity was recovered in the faeces and 11.3% of the dose was excreted in the urine.
Ombitasvir and paritaprevir do not inhibit organic anion transporter (OAT1) in vivo and are not expected to inhibit organic cation transporters (OCT1 and OCT2), organic anion transporters (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations. Ritonavir does not inhibit OAT1 and is not expected to inhibit OCT2, OAT3, MATE1 and MATE2K at clinically relevant concentrations.
Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, a 10 year increase or decrease in age from 54 years (median age in the Phase 3 studies) would result in approximately 10% change in ombitasvir exposures, and ≤20% change in paritaprevir exposures. There is no pharmacokinetic information in patients >75 years.
Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, female subjects would have approximately 55% higher, 100% higher and 15% higher ombitasvir, paritaprevir and ritonavir exposures than male subjects. However, no dose-adjustment based on gender is warranted. A 10 kg change in body weight from 76 kg (median weight in the Phase 3 studies) would results in <10% change in ombitasvir exposures, and no change in paritaprevir exposures. Body weight is not a significant predictor of ritonavir exposures.
Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, Asian subjects had 18% to 21% higher ombitasvir exposures, and 37% to 39% higher paritaprevir exposures than non-Asian subjects. The ritonavir exposures were comparable between Asians and non-Asians.
The changes in ombitasvir, paritaprevir, and ritonavir exposures in subjects with mild, moderate and severe renal impairment are not considered to be clinically significant. Limited data in patients with endstage renal disease indicate no clinically significant changes in exposure also in this patient group. No dose adjustment of Viekirax with and without dasabuvir is required for patients with mild, moderate or severe renal impairment , or end-stage-renal disease on dialysis (see section 4.2).
Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg, with or without dasabuvir 400 mg were evaluated in subjects with mild (CrCl: 60 to 89 ml/min), moderate (CrCl: 30 to 59 ml/min) and severe (CrCl: 15 to 29 ml/min) renal impairment.
Compared to the subjects with normal renal function, ombitasvir exposures were comparable in subjects with mild, moderate and severe renal impairment. Compared to the subjects with normal renal function, paritaprevir Cmax values were comparable, but AUC values were 19%, 33% and 45% higher in mild, moderate and severe renal impairment, respectively. Ritonavir plasma concentrations increased when renal function was reduced: Cmax and AUC values were 26% to 42% higher, 48% to 80% higher and 66% to 114% higher in subjects with mild, moderate and severe renal impairment, respectively.
Following administration of Viekirax, the changes in ombitasvir, paritaprevir, and ritonavir exposures in subjects with mild, moderate and severe renal impairment were similar to those observed when Viekirax was administered with dasabuvir, and are not considered to be clinically significant.
Following administration of Viekirax and dasabuvir:
Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg, with dasabuvir 400 mg were evaluated in non-HCV infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment.
In subjects with mild hepatic impairment, paritaprevir, ritonavir and ombitasvir mean Cmax and AUC values decreased by 29% to 48%, 34% to 38% and up to 8%, respectively, compared to subjects with normal hepatic function.
In subjects with moderate hepatic impairment, ombitasvir and ritonavir mean Cmax and AUC values decreased by 29% to 30% and 30 to 33%, respectively, while paritaprevir mean Cmax and AUC values increased by 26% to 62% compared to subjects with normal hepatic function. (see sections 4.2, 4.4, and 4.8).
In subjects with severe hepatic impairment, paritaprevir mean Cmax and AUC values increased by 3.2-to 9.5-fold; ritonavir mean Cmax values were 35% lower and AUC values were 13% higher and ombitasvir mean Cmax and AUC values decreased by 68% and 54%, respectively, compared to subjects with normal hepatic function, therefore, Viekirax must not be used in patients with severe hepatic impairment (see sections 4.2 and 4.4).
In HCV-infected subjects, in comparison to those without cirrhosis, paritaprevir AUC increased to 2.2- to 2.4-fold for those with compensated cirrhosis (Child-Pugh A) and 3- to 4-fold for those with Child-Pugh B cirrhosis.
Following administration of Viekirax:
Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg were not evaluated in subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (ChildPugh C) hepatic impairment. Results from the pharmacokinetic evaluation of the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg, with dasabuvir 400 mg can be extrapolated to the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg.
The pharmacokinetics of Viekirax in paediatric patients has not been established (see section 4.2).
Ombitasvir and its major inactive human metabolites (M29, M36) were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
Ombitasvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (150 mg/kg/day), resulting in ombitasvir AUC exposures approximately 26-fold higher than those in humans at the recommended clinical dose of 25 mg.
Similarly, ombitasvir was not carcinogenic in a 2-year rat study up to the highest dose tested (30 mg per kg per day), resulting in ombitasvir exposures approximately 16-fold higher than those in humans at 25 mg.
Ombitasvir has shown malformations in rabbits at maximal feasible exposures 4-fold higher than the AUC exposure at recommended clinical dose. Malformations at low incidence were observed mainly in the eyes (microphthalmia) and teeth (absent incisors). In mice, an increased incidence of open eye lid was present in foetuses of dams administered ombitasvir; however, the relationship to treatment with ombitasvir is uncertain. The major, inactive human metabolites of ombitasvir were not teratogenic in mice at exposures approximately 26 times higher than in humans at the recommended clinical dose. Ombitasvir had no effect on fertility when evaluated in mice.
Unchanged ombitasvir was the predominant component observed in the milk of lactating rats, without effect on nursing pups. Ombitasvir-derived material was minimally transferred through the placenta in pregnant rats.
Paritaprevir was positive in an in vitro human chromosome aberration test. Paritaprevir was negative in a bacterial mutation assay, and in two in vivo genetic toxicology assays (rat bone marrow micronucleus and rat liver Comet tests).
Paritaprevir/ritonavir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (300 mg/30 mg/kg/day), resulting in paritaprevir AUC exposures approximately 38-fold higher than those in humans at the recommended dose of 150 mg. Similarly, paritaprevir/ritonavir was not carcinogenic in a 2-year rat study up to the highest dosage tested (300 mg/30 mg/kg/day), resulting in paritaprevir AUC exposures approximately 8-fold higher than those in humans at 150 mg.
Paritaprevir/ritonavir has shown malformations (open eye lids) at a low incidence in mice at exposures 32/8-fold higher than the exposure in humans at the recommended clinical dose. Paritaprevir/ritonavir had no effects on embryo-foetal viability or on fertility when evaluated in rats at exposures 2- to 8-fold higher than the exposure in humans at the recommended clinical dose.
Paritaprevir and its hydrolysis product M13 were the predominant components observed in the milk of lactating rats, without effect on nursing pups. Paritaprevir -derived material was minimally transferred through the placenta in pregnant rats.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
