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VIEKIRA XR(dasabuvir, ombitasvir, paritaprevir, and ritonavir)extended-release tablets(二十七)
ce of ritonavir did not affect the antiviral activity of paritaprevir.
Combination Antiviral Activity
eva luation of pairwise combinations of ombitasvir, paritaprevir, dasabuvir and ribavirin in HCV genotype 1 replicon cell culture assays showed no evidence of antagonism in antiviral activity.
Resistance
In Cell Culture
Exposure of HCV genotype 1a and 1b replicons to ombitasvir, paritaprevir or dasabuvir resulted in the emergence of drug resistant replicons carrying amino acid substitutions in NS5A, NS3, or NS5B, respectively. Amino acid substitutions in NS5A, NS3, or NS5B selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterized in genotype 1a or 1b replicons.
For dasabuvir, in HCV genotype 1a replicons single NS5B substitutions C316Y, M414I/T, E446K/Q, Y448C/H, A553T, G554S, S556G/R, and Y561H reduced dasabuvir antiviral activity by 8- to 1,472-fold. In genotype 1b replicons, single NS5B substitutions C316H/N/Y, S368T, N411S, M414I/T, Y448C/H, A553V, S556G and D559G reduced dasabuvir antiviral activity by 5- to 1,569-fold.
For ombitasvir, in HCV genotype 1a replicons single NS5A substitutions M28T/V, Q30E/R, L31V, H58D, and Y93C/H/L/N reduced ombitasvir antiviral activity by 58- to 67,000-fold. In genotype 1b replicons, single NS5A substitutions L28T, L31F/V, and Y93H reduced ombitasvir antiviral activity by 8- to 661-fold. In general, combinations of ombitasvir resistance-associated substitutions in HCV genotype 1a or 1b replicons further reduced ombitasvir antiviral activity.
For paritaprevir, in HCV genotype 1a replicons single NS3 substitutions F43L, R155G/K/S, A156T, and D168A/E/F/H/N/V/Y reduced paritaprevir antiviral activity by 7- to 219-fold. An NS3 Q80K substitution in a genotype 1a replicon reduced paritaprevir antiviral activity by 3-fold. Combinations of V36M, Y56H, or E357K with R155K or D168 substitutions reduced the activity of paritaprevir by an additional 2- to 7-fold relative to the single R155K or D168 substitutions in genotype 1a replicons. In genotype 1b replicons single NS3 substitutions A156T and D168A/H/V reduced paritaprevir antiviral activity by 7- to 159-fold. The combination of Y56H with D168 substitutions reduced the activity of paritaprevir by an additional 16- to 26-fold relative to the single D168 substitutions in genotype 1b replicons.
In Clinical Studies
In a pooled analysis of subjects treated with regimens containing dasabuvir, ombitasvir, paritaprevir, and ritonavir with or without ribavirin (for 12 or 24 weeks) in Phase 2b and Phase 3 clinical trials, resistance analyses were conducted for 64 subjects who experienced virologic failure (20 with on-treatment virologic failure, 44 with post-treatment relapse). Treatment-emergent substitutions observed in the viral populations of these subjects are shown in TABLE 9. Treatment-emergent substitutions were detected in all 3 HCV drug targets in 30/57 (53%) HCV genotype 1a infected subjects, and 1/6 (17%) HCV genotype 1b infected subjects.
Table 9. Treatment-Emergent Amino Acid Substitutions in the Pooled Analysis of the Components of VIEKIRA XR with and without Ribavirin Regimens (12- or 24-week durations) in Phase 2b and Phase 3 Clinical Trials
Target Emergent Amino Acid Substitutions Genotype 1a
N = 58a
% (n) Genotype 1b
N = 6
% (n)
NS3 Any of the following NS3 substitutions: V36A/M/T,
F43L, V55I, Y56H, Q80L, I132V, R155K, A15 |
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