Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Pharmacotherapeutic group: Antivirals for systemic use, Direct acting antivirals, Antivirals for treatment of HCV infections
ATC code: J05AP54
ZEPATIER combines two direct-acting antiviral agents with distinct mechanisms of action and nonoverlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.
Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly.
Grazoprevir is an inhibitor of the 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. In a biochemical assay, grazoprevir inhibited the proteolytic activity of the recombinant NS3/4A protease enzymes from HCV genotypes 1a, 1b, 3 and 4a with IC50 values ranging from 4 to 690 pM.
The EC50 values of elbasvir and grazoprevir against full-length or chimeric replicons encoding NS5A or NS3 sequences from reference sequences and clinical isolates are presented in Table 5.
Table 5. Activities of elbasvir and grazoprevir in GT1a, GT1b and GT4 reference sequences and clinical isolates in replicon cells:
| Elbasvir | Grazoprevir | |
|---|---|---|
| Reference | EC50 nM | |
| GT1a (H77) | 0.004 | 0.4 |
| GT1b (con 1) | 0.003 | 0.5 |
| GT4 (ED43) | 0.0003 | 0.3 |
| Clinical Isolates | Median EC50 (range) nM | |
| GT1a | 0.005 (0.003-0.009)a | 0.8 (0.4-5.1)d |
| GT1b | 0.009 (0.005-0.01)b | 0.3 (0.2-5.9)e |
| GT4 | 0.0007 (0.0002-34)c | 0.2 (0.11-0.33)a |
Number of isolates tested: a=5, b=4, c=14, d=10, e=9
HCV replicons with reduced susceptibility to elbasvir and grazoprevir have been selected in cell culture for genotypes 1a, 1b and 4.
For elbasvir, in HCV genotype 1a replicons, single NS5A substitutions Q30D/E/H/R, L31M/V and Y93C/H/N reduced elbasvir antiviral activity by 6- to 2,000-fold. In genotype 1b replicons, single NS5A substitutions L31F and Y93H reduced elbasvir antiviral activity by 17-fold. In genotype 4 replicons, single NS5A substitutions L30S, M31V, and Y93H reduced elbasvir antiviral activity by 3- to 23-fold. In general, in HCV genotype 1a, 1b or 4 combinations of elbasvir resistance-associated substitutions further reduced elbasvir antiviral activity.
For grazoprevir, in HCV genotype 1a replicons, single NS3 substitutions D168A/E/G/S/V reduced grazoprevir antiviral activity by 2- to 81-fold. In genotype 1b replicons, single NS3 substitutions F43S, A156S/T/V, and D168A/G/V reduced grazoprevir antiviral activity by 3- to 375-fold. In genotype 4 replicons, single NS3 substitutions D168A/V reduced grazoprevir antiviral activity by 110- to 320-fold. In general, in HCV genotype 1a, 1b or 4 replicons, combinations of grazoprevir resistance-associated substitutions further reduced grazoprevir antiviral activity.
In a pooled analysis of subjects treated with regimens containing elbasvir/grazoprevir or elbasvir + grazoprevir with or without ribavirin in Phase 2 and 3 clinical studies, resistance analyses were conducted for 50 subjects who experienced virologic failure and had sequence data available (6 with on-treatment virologic failure, 44 with post-treatment relapse).
Treatment-emergent substitutions observed in the viral populations of these subjects based on genotypes are shown in Table 6. Treatment-emergent substitutions were detected in both HCV drug targets in 23/37 (62 %) genotype 1a, 1/8 (13 %) genotype 1b and 2/5 (40 %) genotype 4 subjects.
Table 6. Treatment-emergent amino acid substitutions in the pooled analysis of ZEPATIER with and without ribavirin regimens in Phase 2 and Phase 3 clinical studies:
| Target | Emergent Amino Acid Substitutions | Genotype 1a N=37 % (n) | Genotype 1b N=8 % (n) | Genotype 4 N=5 % (n) |
|---|---|---|---|---|
| NS5A | Any of the following NS5A substitutions: M/L28A/G/T/S* Q30H/K/R/Y, L/M31F/M/I/V, H/P58D, Y93H/N/S | 81% (30) | 88% (7) | 100% (5) |
| M/L28A/G/T/S | 19% (7) | 13% (1) | 60% (3) | |
| Q30H/K/Y | 14% (5) | -- | -- | |
| Q30R | 46% (17) | -- | -- | |
| L/M31M/F/I/V† | 11% (4) | 25% (2) | 40% (2) | |
| H/P58D‡ | 5% (3) | -- | 20% (1) | |
| Y93H/N/S | 14% (5) | 63% (5) | 20% (1) | |
| NS3 | Any of the following NS3 substitutions: V36L/M, Y56F/H, V107I, R155I/K, A156G/M/T/V, V158A, D168A/C/E/G/N/V/Y, V170I | 78% (29) | 25% (2) | 40% (2) |
| V36L/M | 11% (4) | -- | -- | |
| Y56F/H | 14% (5) | 13% (1) | -- | |
| V107I | 3% (1) | 13% (1) | -- | |
| R155I/K | 5% (2) | -- | -- | |
| A156T | 27% (10) | 13% (1) | 20% (1) | |
| A156G/V/M | 8% (3) | -- | 60% (3) | |
| V158A | 5% (2) | -- | -- | |
| D168A | 35% (13) | -- | 20% (1) | |
| D168C/E/G/N/V/Y | 14% (5) | -- | 20% (1) | |
| V170I | -- | -- | 20% (1) |
* Reference sequences for NS5A at amino acid 28 are M (genotype 1a) and L (genotype 1b and genotype 4a and 4d).
† Reference sequences for NS5A at amino acid 31 are L (genotype 1a and genotype 1b) and M (genotype 4a and 4d).
‡ Reference sequences for NS5A at amino acid 58 are H (genotype 1a) and P (genotype 1b and genotype 4a and 4d).
Elbasvir is active in vitro against genotype 1a NS5A substitutions, M28V and Q30L, genotype 1b substitutions, L28M/V, R30Q, L31V, Y93C, and genotype 4 substitution, M31V, which confer resistance to other NS5A inhibitors. In general, other NS5A substitutions conferring resistance to NS5A inhibitors may also confer resistance to elbasvir. NS5A substitutions conferring resistance to elbasvir may reduce the antiviral activity ofother NS5A inhibitors.
Grazoprevir is active in vitro against the following genotype 1a NS3 substitutions which confer resistance to other NS3/4A protease inhibitors: V36A/L/M, Q41R, F43L, T54A/S, V55A/I, Y56F, Q80K/R, V107I, S122A/G/R/T, I132V, R155K, A156S, D168N/S, I170T/V. Grazoprevir is active in vitro against the following genotype 1b NS3 substitutions conferring resistance to other NS3/4A protease inhibitors: V36A/I/L/M, Q41L/R, F43S, T54A/C/G/S, V55A/I, Y56F, Q80L/R, V107I, S122A/G/R, R155E/K/N/Q/S, A156G/S, D168E/N/S, V170A/I/T. Some NS3 substitutions at A156 and at D168 confer reduced antiviral activity to grazoprevir as well as to other NS3/4A protease inhibitors.
The substitutions associated with resistance to NS5B inhibitors do not affect the activity of elbasvir or grazoprevir.
The persistence of elbasvir and grazoprevir treatment-emergent amino acid substitutions in NS5A, and NS3, respectively, was assessed in genotype 1-infected subjects in Phase 2 and 3 studies whose virus had treatment-emergent resistance-associated substitution in the drug target, and with available data through at least 24 weeks post-treatment using population (or Sanger) sequencing.
Viral populations with treatment-emergent NS5A resistance-associated substitutions were generally more persistent than NS3 resistance associated substitutions. Among genotype 1a-infected subjects, NS5A resistance-associated substitutions persisted at detectable levels at follow-up week 12 in 95% (35/37) of subjects and in 100% (9/9) of subjects with follow-up week 24 data. Among genotype 1binfected subjects, NS5A resistance-associated substitutions persisted at detectable levels in 100% (7/7) of subjects at follow-up week 12 and in 100% (3/3) of subjects with follow-up week 24 data. Among genotype 1a-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 31% (4/13) of subjects.
Among genotype 1a-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 31% (4/13) of subjects. Among genotype 1b-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 50% (½) of subjects.
Due to the limited number ofgenotype 4-infected subjects with treatment emergent NS5A and NS3 resistance associated substitutions, trends in persistence of treatment emergent substitutions in this genotype could not be established.
The long-term clinical impact of the emergence or persistence of virus containing ZEPATIER resistance-associated substitutions is unknown.
In pooled analyses of subjects who achieved SVR12 or met criteria for virologic failure, the prevalence and impact of NS5A polymorphisms (including M28T/A, Q30E/H/R/G/K/D, L31M/V/F, H58D, and Y93C/H/N) and NS3 polymorphisms (substitutions at positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170. and 175) that confer greater than 5-fold reduction of elbasvir and grazoprevir antiviral activity respectively in vitro were evaluated. The observed treatment response differences by treatment regimen in specific patient populations in the presence or absence of baseline NS5A or NS3 polymorphisms are summarised in Table 7.
Table 7. SVR in GT1a-, GT1b- or treatment-experienced GT4-infected subjects bearing baseline NS5A or NS3 polymorphisms:
| SVR12 by Treatment Regimen | ||||
|---|---|---|---|---|
| ZEPATIER, 12 Weeks | ZEPATIER + RBV, 16 Weeks | |||
| Patient Population | Subjects without baseline NS5A polymorphisms,* % (n/N) | Subjects with baseline NS5A polymorphisms,* % (n/N) | Subjects without baseline NS5A polymorphisms,* % (n/N) | Subjects with baseline NS5A polymorphisms,* % (n/N) |
| GT1a† | 97% (464/476) | 53% (16/30) | 100% (51/51) | 100% (4/4) |
| GT1b‡ | 99% (259/260) | 92% (36/39) | ||
| Subjects without baseline NS3 polymorphisms,¶ % (n/N) | Subjects with baseline NS3 polymorphisms,¶ % (n/N) | |||
| GT4 (treatment- experienced)# | 86% (25/29) | 100% (7/7) | ||
* NS5A polymorphisms (conferring > 5-fold potency loss to elbasvir) included M28T/A, Q30E/H/R/G/K/D, L31M/V/F, H58D, and Y93C/H/N
† Overall prevalence of GT1a-infected subjects with baseline NS5A polymorphisms in the pooled analyses was 7% (55/825)
‡ Overall prevalence of GT1b-infected subjects with baseline NS5A polymorphisms in the pooled analyses was 14% (74/540)
¶ NS3 polymorphisms considered were any amino acid substitution at positions 36, 54, 55, 56, 80. 107, 122, 132, 155, 156, 158, 168, 170. and 175
# Overall prevalence of GT4-infected subjects with baseline NS3 polymorphisms in the pooled analyses was 19% (7/36)
The safety and efficacy of elbasvir/grazoprevir (co-administered as a fixed-dose combination; EBR/GZR) or elbasvir + grazoprevir (co-administered as single agents; EBR + GZR) were evaluated in 8 adult clinical studies and 1 paediatric clinical study in approximately 2,000 subjects (see Table 8).
Table 8. Studies conducted with ZEPATIER:
| Study | Population | Study Arms and Duration (Number of Subjects Treated) | Additional Study Details |
|---|---|---|---|
| C-EDGE TN (double-blind) | GT 1, 4, 6 TN with or without cirrhosis | • EBR/GZR* for 12 weeks (N=316) • Placebo for 12 weeks (N=105) | Placebo-controlled study in which subjects were randomised in a 3:1 ratio to: EBR/GZR for 12 weeks (immediate treatment group [ITG]) or placebo for 12 weeks followed by open-label treatment with EBR/GZR for 12 weeks (deferred treatment group (DTG)). |
| C-EDGE COINFECTION (open-label) | GT 1, 4, 6 TN with or without cirrhosis HCV/HIV-1 co-infection | • EBR/GZR for 12 weeks (N=218) | |
| C-SURFER (double-blind) | GT 1 TN or TE with or without cirrhosis Chronic Kidney Disease | • EBR* + GZR* for 12 weeks (N=122) • Placebo for 12 weeks (N=113) | Placebo-controlled study in subjects with CKD Stage 4 (eGFR 15-29 mL/min/1.73 m²) or Stage 5 (eGFR < 15 mL/min/1.73 m²), including subjects on hemodialysis, Subjects were randomised in a 1:1 ratio to one of the following treatment groups: EBR + GZR for 12 weeks (ITG) or placebo for 12 weeks followed by open-label treatment with EBR/GZR for 12 weeks (DTG). In addition, 11 subjects received open-label EBR + GZR for 12 weeks (intensive PK arm). |
| C-WORTHY (open-label) | GT 1, 3 TN with or without cirrhosis TE Null Responder with or without cirrhosis TN HCV/HIV-1 co-infection without cirrhosis | • EBR* + GZR* for 8, 12, or 18 weeks (N=31, 136, and 63, respectively) • EBR* + GZR* + RBV† for 8, 12, or 18 weeks (N=60, 152, and 65, respectively) | Multi-arm, multi-stage study. Subjects with GT 1b infection without cirrhosis were randomised in a 1:1 ratio to EBR + GZR with or without RBV for 8 weeks. TN subjects with GT 3 infection without cirrhosis were randomised to EBR + GZR with RBV for 12 or 18 weeks. TN subjects with GT 1 infection with or without cirrhosis (with or without HCV/HIV-1 co-infection) or who were peg-IFN + RBV null responders, were randomised to EBR + GZR with or without RBV for 8, 12 or 18 weeks. |
| C-SCAPE (open-label) | GT 4, 6 TN without cirrhosis | • EBR* + GZR* for 12 weeks (N=14) • EBR* + GZR* + RBV† for 12 weeks (N=14) | Subjects were randomised in a 1:1 ratio to the study arms. |
| C-EDGE TE (open-label) | GT 1, 4, 6 TE with or without cirrhosis, and with or without HCV/HIV-1 co-infection | • EBR/GZR for 12 or 16 weeks (N=105 and 105, respectively) • EBR/GZR + RBV† for 12 or 16 weeks (N=104 and 106, respectively) | Subjects were randomised in a 1:1:1:1 ratio to the study arms. |
| C-SALVAGE (open-label) | GT 1 TE with HCV protease inhibitor regimen‡ with or without cirrhosis | • EBR* + GZR* + RBV† for 12 weeks (N=79) | Subjects who had failed prior treatment with boceprevir, simeprevir, or telaprevir in combination with peg-IFN + RBV received EBR + GZR with RBV for 12 weeks. |
| C-EDGE COSTAR (double-blind) | GT 1, 4, 6 TN with or without cirrhosis Opiate agonist therapy | • EBR/GZR for 12 weeks (N=201) • Placebo for 12 weeks (N=100) | Placebo-controlled study in which subjects were randomised in a 2:1 ratio to EBR/GZR for 12 weeks (ITG) or placebo for 12 weeks followed by open-label treatment with EBR/GZR for 12 weeks (DTG). Subjects were not excluded or discontinued from the trial based on a positive urine drug screen. |
| MK-5172A-079 (open-label) | GT 1, 4 TN or TE pediatric subjects | • EBR/GZR for 12 weeks (N=22) | Non-randomised, single-arm, open-label study in treatment-naïve or treatment-experienced pediatric subjects, including 22 subjects 12 years to less than 18 years of age, with chronic Hepatitis C (CHC) GT 1 or 4 infection without cirrhosis who received EBR/GZR for 12 weeks. |
GT = Genotype
TN = Treatment-Naïve
TE = Treatment-Experienced (failed prior treatment with interferon [IFN] or peginterferon alfa [peg-IFN] with or without ribavirin (RBV) or were intolerant to prior therapy)
* EBR = elbasvir 50 mg; GZR = grazoprevir 100 mg; EBR/GZR = co-administered as a fixed-dose combination; EBR + GZR = co-administered as separate single agents
† RBV was administered at a total daily dose of 800 mg to 1,400 mg based on weight (see section 4.2)
‡ Failed prior treatment with boceprevir, telaprevir, or simeprevir in combination with peg-IFN + RBV
Sustained virologic response (SVR) was the primary endpoint in all studies and was defined as HCV RNA less than the lower limit of quantification (LLOQ: 15 HCV RNA IU/mL except in C-WORTHY and C-SCAPE [25 HCV RNA IU/mL]) at 12 weeks after the cessation of treatment (SVR12).
Among genotype 1b/1 other-infected subjects, the median age was 55 years (range: 22 to 82); 61% were male; 60% were White; 20% were Black or African American; 6% were Hispanic or Latino; 82% were treatment-naïve subjects; 18% were treatment-experienced subjects; mean body mass index was 26 kg/m²; 64% had baseline HCV RNA levels greater than 800.000 IU/mL; 22% had cirrhosis; 71% had non-C/C IL28B alleles (CT or TT); 18% had HCV/HIV-1 co-infection.
Treatment outcomes in genotype 1b-infected subjects treated with elbasvir/grazoprevir for 12 weeks are presented in Table 9.
Table 9. SVR in genotype 1b†-infected subjects¶:
| Baseline Characteristics | SVR |
|---|---|
| EBR with GZR for 12 weeks (N=312) | |
| Overall SVR | 96% (301/312) |
| Outcome for subjects without SVR | |
| On-treatment virologic failure* | 0% (0/312) |
| Relapse | 1% (4/312) |
| Other‡ | 2% (7/312) |
| SVR by cirrhosis status | |
| Non-cirrhotic | 95% (232/243) |
| Cirrhotic | 100% (69/69) |
† Includes four subjects infected with genotype 1 subtypes other than 1a or 1b.
¶ Includes subjects from C-EDGE TN, C-EDGE COINFECTION, C-EDGE TE, C-WORTHY and C-SURFER.
* Includes subjects with virologic breakthrough.
‡ Other includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.
Among genotype 1a-infected subjects, the median age was 54 years (range: 19 to 76); 71% were male; 71% were White; 22% were Black or African American; 9% were Hispanic or Latino; 74% were treatment-naïve subjects; 26% were treatment-experienced subjects; mean body mass index was 27 kg/m²; 75% had baseline HCV RNA levels greater than 800.000 IU/mL; 23% had cirrhosis; 72% had non-C/C IL28B alleles (CT or TT); 30% had HCV/HIV-1 co-infection.
Treatment outcomes in genotype 1a-infected subjects treated with elbasvir/grazoprevir for 12 weeks or elbasvir/grazoprevir with ribavirin for 16 weeks are presented in Table 10.
Table 10. SVR in genotype 1a-infected subjects¶:
| Baseline Characteristics | SVR | |
|---|---|---|
| EBR with GZR 12 Weeks N=519 | EBR with GZR + RBV 16 Weeks N=58 | |
| Overall SVR | 93% (483/519) | 95% (55/58) |
| Outcome for subjects without SVR | ||
| On-treatment virologic failure* | 1% (3/519) | 0% (0/58) |
| Relapse | 4% (23/519) | 0% (0/58) |
| Other‡ | 2% (10/519) | 5% (3/58) |
| SVR by cirrhosis status | ||
| Non-cirrhotic | 93% (379/408) | 92% (33/36) |
| Cirrhotic | 94% (104/111) | 100% (22/22) |
| SVR by presence of baseline NS5A resistance-associated polymorphisms†,§ | ||
| Absent | 97% (464/476) | 100% (51/51) |
| Present | 53% (16/30) | 100% (4/4) |
| SVR by baseline HCV RNA | ||
| ≤800.000 IU/ml | 98% (135/138) | 100% (9/9) |
| >800.000 IU/ml | 91% (348/381) | 94% (46/49) |
¶ ΣIncludes subjects from C-EDGE TN, C-EDGE COINFECTION, C-EDGE TE, C-WORTHY and C-SURFER.
* Includes subjects with virologic breakthrough.
‡ Other includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.
† Includes subjects with baseline sequencing data and who either achieved SVR12 or met criteria for virologic failure
§ GT1a NS5A polymorphisms: M28T/A, Q30E/H/R/G/K/D, L31M/V/F, H58D, and Y93C/H/N.
Among genotype 4-infected subjects, the median age was 51 years (range: 28 to 75); 66% were male; 88% were White; 8% were Black or African American; 11% were Hispanic or Latino; 77% were treatment-naïve subjects; 23% were treatment-experienced subjects; mean body mass index was 25 kg/m²; 56% had baseline HCV RNA levels greater than 800.000 IU/mL; 22% had cirrhosis; 73% had non-C/C IL28B alleles (CT or TT); 40% had HCV/HIV-1 co-infection.
Treatment outcomes in genotype 4-infected subjects treated with elbasvir/grazoprevir for 12 weeks or elbasvir/grazoprevir with ribavirin for 16 weeks are presented in Table 11.
Table 11. SVR in genotype 4-infected subjects¶:
| Baseline Characteristics | SVR | |
|---|---|---|
| EBR with GZR 12 Weeks N=65 | EBR with GZR + RBV 6 Weeks N=8 | |
| Overall SVR | 94% (61/65) | 100% (8/8) |
| Outcome for subjects without SVR | ||
| On-treatment virologic failure* | 0% (0/65) | 0% (0/8) |
| Relapse† | 3% (2/65) | 0% (0/8) |
| Other‡ | 3% (2/65) | 0% (0/8) |
| SVR by cirrhosis status | ||
| Non-cirrhotic§ | 96% (51/53) | 100% (4/4) |
| Cirrhotic | 83% (10/12) | 100% (4/4) |
| SVR by baseline HCV RNA | ||
| ≤800.000 IU/ml‡ | 93% (27/29) | 100% (3/3) |
| >800.000 IU/ml† | 94% (34/36) | 100% (5/5) |
¶ Includes subjects from C-EDGE TN, C-EDGE COINFECTION, C-EDGE TE and C-SCAPE.
* Includes subjects with virologic breakthrough.
† Both relapsers had baseline HCV RNA >800.000 IU/mL
‡ Both subjects who failed to achieve SVR for reasons other than virologic failure had baseline HCV RNA ≤800.000 IU/mL.
§ Includes 1 subject with cirrhosis status of “unknown” in C-SCAPE.
In the C-SURFER study, overall SVR was achieved in 94% (115/122) of subjects receiving EBR + GZR for 12 weeks.
The efficacy of ZEPATIER was evaluated in an open-label clinical study in 22 paediatric subjects 12 years to less than 18 years of age who received ZEPATIER for 12 weeks. HCV GT1a infected subjects with one or more baseline NS5A resistance-associated substitutions were excluded from study participation.
In this study, treatment-naïve or treatment-experienced subjects 12 years to less than 18 years of age with genotype 1 or 4 CHC, without cirrhosis, were treated with ZEPATIER for 12 weeks. The median age was 13.5 years (range: 12 to 17); 50% were female; 95% were White; the weight range was 28.1 kg to 96.5 kg; 95.5% had genotype 1 and 4.5% had genotype 4; 63.6% were treatment-naïve,
36.4% were treatment-experienced; 45.5% had baseline HCV RNA levels greater than 800,000 IU/mL. The overall SVR12 rate was 100% (22/22). The safety, pharmacokinetics and efficacy observed in this study were comparable to those observed in adults.
Following administration of elbasvir/grazoprevir to HCV-infected subjects, elbasvir peak plasma concentrations occur at a median Tmax of 3 hours (range of 3 to 6 hours); grazoprevir peak plasma concentrations occur at a median Tmax of 2 hours (range of 30 minutes to 3 hours). For elbasvir, the absolute bioavailability is estimated to be 32%. For grazoprevir, the absolute bioavailability after a 200 mg single dose ranged from 15-27% and after multiple 200 mg doses ranged from 20-40%.
Relative to fasting conditions, the administration of a single dose of elbasvir/grazoprevir with a highfat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC0-inf and Cmax of approximately 11% and 15%, respectively, and increases in grazoprevir AUC0-inf and Cmax of approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, elbasvir/grazoprevir may be taken without regard to food.
Elbasvir pharmacokinetics are similar in healthy subjects and HCV-infected subjects. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects.
Based on the population pharmacokinetic modeling in non-cirrhotic, HCV-infected subjects, the geometric mean steady-state elbasvir AUC0-24 and Cmax at 50 mg were 2,180 nM•hr and 137 nM, respectively, and the geometric mean steady-state grazoprevir AUC0-24 and Cmax at 100 mg were 1,860 nM•hr and 220 nM, respectively. Following once daily administration of elbasvir/grazoprevir to HCV-infected subjects, elbasvir and grazoprevir reached steady state within approximately 6 days.
Elbasvir and grazoprevir are extensively bound (>99.9% and 98.8%, respectively) to human plasma proteins. Both elbasvir and grazoprevir bind to human serum albumin and α1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
The geometric mean apparent terminal half-life (% geometric mean coefficient of variation) is approximately 24 (24%) hours at 50 mg elbasvir and approximately 31 (34%) hours at 100 mg grazoprevir in HCV-infected subjects.
Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma.
The primary route of elimination of elbasvir and grazoprevir is through faeces with almost all (>90%) of the radiolabeled dose recovered in faeces compared to <1% in urine.
Elbasvir pharmacokinetics were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects.
In non-HCV-infected subjects with severe renal impairment (eGFR <30 mL/min/1.73 m²) who were not on dialysis, elbasvir and grazoprevir AUC values were increased by 86% and 65%, respectively, compared to non-HCV-infected subjects with normal renal function (eGFR >80 mL/min/1.73 m²). In non-HCV-infected subjects with dialysis-dependent, severe renal impairment, elbasvir and grazoprevir AUC values were unchanged compared to subjects with normal renal function. Concentrations of elbasvir were not quantifiable in the dialysate samples. Less than 0.5% of grazoprevir was recovered in dialysate over a 4-hour dialysis session.
In population pharmacokinetic analysis in HCV-infected patients, elbasvir and grazoprevir AUCs were 25% and 10% higher, respectively, in dialysis-dependent patients and 46% and 40% higher, respectively, in non-dialysis-dependent patients with severe renal impairment compared to elbasvir and grazoprevir AUC in patients without severe renal impairment.
In non-HCV-infected subjects with mild hepatic impairment (Child-Pugh A [CP-A], score of 5-6), elbasvir AUC0-inf was decreased by 40% and grazoprevir steady-state AUC0-24 was increased 70% compared to matched healthy subjects.
In non-HCV-infected subjects with moderate hepatic impairment (Child-Pugh B [CP-B], score of 7-9), and severe hepatic impairment (Child-Pugh C [CP-C], score of 10-15) elbasvir AUC decreased by 28% and 12%, respectively, while the grazoprevir steady-state AUC0-24 was increased 5-fold and 12-fold respectively, compared to matched healthy subjects (see sections 4.2 and 4.3).
Population PK analyses of HCV-infected patients in Phase 2 and 3 studies demonstrated that grazoprevir steady-state AUC0-24 increased by approximately 65% in HCV-infected patients with compensated cirrhosis (all with CP-A) compared to HCV-infected non-cirrhotic patients, while elbasvir steady-state AUC was similar (see section 4.2).
The pharmacokinetics of elbasvir and grazoprevir have been evaluated in 22 paediatric subjects 12 years of age and older who received a daily dose of ZEPATIER (50 mg elbasvir/100 mg grazoprevir). Elbasvir and grazoprevir exposures in paediatric subjects were comparable to those observed in adults.
In paediatric subjects 12 years of age and older, the geometric mean steady-state elbasvir AUC0-24 and Cmax at 50 mg were 2,410 nM•hr and 190 nM, respectively, and the geometric mean steady-state grazoprevir AUC0-24 and Cmax at 100 mg were 1,450 nM•hr and 246 nM, respectively.
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects ≥65 years of age compared to subjects less than 65 years of age. These changes are not clinically relevant; therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on age (see sections 4.2 and 4.4).
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males. These changes are not clinically relevant; therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on sex (see section 4.4).
In population pharmacokinetic analyses, there was no effect of weight on elbasvir pharmacokinetics. Grazoprevir AUC is estimated to be 15% higher in a 53 kg subject compared to a 77 kg subject. This change is not clinically relevant for grazoprevir. Therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on weight/BMI (see section 4.4).
In population pharmacokinetic analyses, elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Whites. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Whites and Black/African Americans. These changes are not clinically relevant; therefore, no dose adjustment of elbasvir/grazoprevir is recommended based on race/ethnicity (see section 4.4).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction and development with grazoprevir or elbasvir. Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Carcinogenicity studies for grazoprevir and elbasvir have not been conducted.
Elbasvir was given to rats and rabbits without eliciting adverse effects on embryofetal or post natal development at up to the highest doses tested (approximately 9- and 17-fold above human exposure in rats and rabbits, respectively). Elbasvir has been shown to cross the placenta in rats and rabbits. Elbasvir was excreted into the milk of lactating rats with concentrations 4-fold that of the maternal plasma concentrations.
Grazoprevir was given to rats and rabbits without eliciting adverse effects on embryofetal or post natal development at up to highest doses tested (approximately 79- and 39-fold above human exposure in rats and rabbits, respectively). Grazoprevir has been shown to cross the placenta in rats and rabbits. Grazoprevir was excreted into the milk of lactating rats with concentrations <1-fold of the maternal plasma concentrations.
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