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Victrelis

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Victrelis

Victrelis

CLINICAL PHARMACOLOGY

Mechanism Of Action

VICTRELIS is a direct acting antiviral drug against the hepatitis C virus [see Microbiology].

Pharmacodynamics

Evaluation of Effect of VICTRELIS on QTc Interval

The effect of boceprevir 800 mg and 1200 mg on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 36 healthy subjects. In the study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 1200 mg yields a boceprevir maximum exposure increase of approximately 15% which may not cover exposures due to coadministration with strong CYP3A4 inhibitors or use in patients with severe hepatic impairment. However, at the doses studied in the thorough QT study, no apparent concentration-QT relationship was identified. Thus, there is no expectation of a QTc effect under a higher exposure scenario.

Pharmacokinetics

VICTRELIS capsules contain a 1:1 mixture of two diastereomers, SCH534128 and SCH534129. In plasma the diastereomer ratio changes to 2:1, favoring the active diastereomer, SCH534128. Plasma concentrations of boceprevir described below consist of both diastereomers SCH534128 and SCH534129, unless otherwise specified.

In healthy subjects who received 800 mg three times daily alone, boceprevir drug exposure was characterized by AUC(T) of 5408 ng x hr per mL (n=71), Cmax of 1723 ng per mL (n=71), and Cmin of 88 ng per mL (n=71). Pharmacokinetic results were similar between healthy subjects and HCV-infected subjects.

Absorption

Boceprevir was absorbed following oral administration with a median Tmax of 2 hours. Steady state AUC, Cmax, and Cmin increased in a less-than-dose-proportional manner and individual exposures overlapped substantially at 800 mg and 1200 mg, suggesting diminished absorption at higher doses. Accumulation is minimal (0.8-to 1.5-fold) and pharmacokinetic steady state is achieved after approximately 1 day of three times daily dosing.

The absolute bioavailability of boceprevir has not been studied.

Effects of Food on Oral Absorption

VICTRELIS should be administered with food. Food enhanced the exposure of boceprevir by up to 65% at the 800 mg three times daily dose, relative to the fasting state. The bioavailability of boceprevir was similar regardless of meal type (e.g., high-fat vs. low-fat) or whether taken 5 minutes prior to eating, during a meal, or immediately following completion of the meal. Therefore, VICTRELIS may be taken without regard to either meal type or timing of the meal.

Distribution

Boceprevir has a mean apparent volume of distribution (Vd/F) of approximately 772 L at steady state in healthy subjects. Human plasma protein binding is approximately 75% following a single dose of boceprevir 800 mg. Boceprevir is administered as an approximately equal mixture of two diastereomers, SCH534128 and SCH534129, which rapidly interconvert in plasma. The predominant diastereomer, SCH534128, is pharmacologically active and the other diastereomer is inactive.

Metabolism

Studies in vitro indicate that boceprevir primarily undergoes metabolism through the aldo-keto reductase (AKR)-mediated pathway to ketone-reduced metabolites that are inactive against HCV. After a single 800-mg oral dose of 14C-boceprevir, the most abundant circulating metabolites were a diastereomeric mixture of ketone-reduced metabolites with a mean exposure approximately 4-fold greater than that of boceprevir. Boceprevir also undergoes, to a lesser extent, oxidative metabolism mediated by CYP3A4/5.

Drug Interactions

Drug interaction studies were performed with boceprevir and drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of boceprevir on AUC, Cmax and Cmin are summarized in Table 6 (effects of coadministered drugs on boceprevir) and Table 7 (effects of boceprevir on coadministered drugs).

Table 6 : Summary of the Effect of Co-administered Drugs on Boceprevir in Healthy Subjects or HCV Positive Genotype-1 Subjects

Co-administered Drug Co-administered Drug Dose/Schedule Boceprevir Dose/Schedule Ratio Estimate of Boceprevir Pharmacokinetic Parameters (in Combination vs. Alone)
(90% CI of the Ratio Estimate) *
Change in mean Cmax Change in mean AUC Change in mean Cmin
Atazanavir/ Ritonavir 300 mg/100 mg daily x 22 days 800 mg three times daily x 6 days 0.93
(0.80-1.08)
0.95
(0.87-1.05)
0.82
(0.68-0.98)
Atorvastatin 40 mg single dose 800 mg three times daily x 7 days 1.04
(0.89-1.21)
0.95
(0.90-1.01)
N/A
Buprenorphine/Naloxone Buprenorphine: 8-24 mg + Naloxone: 2-6 mg daily x 6 days 800 mg three times daily x 6 days 0.82
(0.71-0.94)
0.88
(0.76-1.02)
0.95
(0.70-1.28)
Cyclosporine 100 mg single dose 800 mg single dose 1.08
(0.97-1.20)
1.16
(1.06-1.26)
N/A
Darunavir/Ritonavir 600 mg/100 mg two times daily x 22 days 800 mg three times daily x 6 days 0.75
(0.67-0.85)
0.68
(0.65-0.72)
0.65
(0.56-0.76)
Diflunisal 250 mg two times daily x 7 days 800 mg three times daily x 12 days 0.86
(0.56-1.32)
0.96
(0.79-1.17)
1.31
(1.04-1.65)
Efavirenz 600 mg daily x 16 days 800 mg three times daily x 6 days 0.92
(0.78-1.08)
0.81
(0.75-0.89)
0.56
(0.42-0.74)
Escitalopram 10 mg single dose 800 mg three times daily x 11 days 0.91
(0.81-1.02)
1.02
(0.96-1.08)
N/A
Etravirine 200 mg two times daily x 11-14 days 800 mg three times daily x 11-14 days 1.10
(0.94-1.29)
1.10
(0.94-1.28)
0.88†
(0.66-1.17)
Ibuprofen 600 mg three times daily x 6 days 400 mg single oral dose 0.94
(0.67-1.32)
1.04
(0.90-1.20)
N/A
Ketoconazole 400 mg two times daily x 6 days 400 mg single oral dose 1.41
(1.00-1.97)
2.31
(2.00-2.67)
N/A
Lopinavir/Ritonavir 400 mg/100 mg two times daily x 22 days 800 mg three times daily x 6 days 0.50
(0.45-0.55)
0.55
(0.49-0.61)
0.43
(0.36-0.53)
Methadone 20-150 mg daily x 6 days 800 mg three times daily x 6 days 0.62
(0.53-0.72)
0.80
(0.69-0.93)
1.03
(0.75-1.42)
Omeprazole 40 mg daily x 5 days 800 mg three times daily x 5 days 0.94
(0.86-1.02)
0.92
(0.87-0.97)
1.17†
(0.97-1.42)
Peginterferon alfa-2b 1.5 mcg/kg subcutaneous weekly x 2 weeks 400 mg three times daily x 1 week 0.88
(0.66-1.18)
1.00*
(0.89-1.13)
N/A
Pravastatin 40 mg single dose 800 mg three times daily x 6 days 0.93
(0.83-1.04)
0.94
(0.88-1.01)
N/A
Raltegravir 400 mg every 12 hours x 6 days 800 mg every 8 hours x 6 days 0.96
(0.88, 1.05)
0.98‡
(0.90, 1.08)
0.74†
(0.47, 1.16)
Rilpivirine 25 mg every 24 hours x 11 days 800 mg three times daily x 11 days 0.98
(0.89, 1.08)
0.94‡
(0.88, 1.00)
1.04†
(0.93, 1.16)
Ritonavir 100 mg daily x 12 days 400 mg three times daily x 15 days 0.73
(0.57-0.93)
0.81
(0.73-0.91)
1.04
(0.62-1.75)
Sirolimus 2 mg single dose 800 mg three times daily x 9 days 0.94
(0.82, 1.07)
0.95‡
(0.89, 1.01)
1.21†
(1.00, 1.47)
Tacrolimus 0.5 mg single dose 800 mg single dose 0.97
(0.84-1.13)
1.00*
(0.95-1.06)
N/A
Tenofovir 300 mg daily x 7 days 800 mg three times daily x 7 days 1.05
(0.98-1.12)
1.08
(1.02-1.14)
1.08
(0.97-1.20)
*No effect = 1.00
† C 8 hours
‡ AUC0-last
N/A = not available

Table 7 : Summary of the Effect of Boceprevir on Co-administered Drugs in Healthy Subjects or HCV Positive Genotype-1 Subjects

Co-administered Drug Co-administered Drug Dose/Schedule Boceprevir Dose/Schedule Ratio Estimate of Co-administered Pharmacokinetic Parameters (in Combination vs. Alone)
(90% CI of the Ratio Estimate) *
Change in mean Cmax Change in mean AUC (T) Change in mean Cmin
Atazanavir/ Ritonavir 300 mg/100 mg daily x 22 days 800 mg three times daily x 6 days Atazanavir: 0.75
(0.64-0.88) Ritonavir: 0.73
(0.64-0.83)
Atazanavir: 0.65§
(0.55-0.78) Ritonavir: 0.64
(0.58-0.72)
Atazanavir: 0.51
(0.44-0.61) Ritonavir: 0.55
(0.45-0.67)
Atorvastatin 40 mg single dose 800 mg three times daily x 7 days 2.66
(1.81-3.90)
2.30¶
(1.84-2.88)
N/A
Buprenorphine/ Naloxone Buprenorphine: 8-24 mg + Naloxone: 2-6 mg daily x 6 days 800 mg three times daily x 6 days Buprenorphine: 1.18
(0.93-1.50) Naloxone: 1.09
(0.79-1.51)
Buprenorphine: 1.19
(0.91-1.57) Naloxone: 1.33
(0.90-1.98)
Buprenorphine: 1.31
(0.95-1.79) Naloxone: N/A
Cyclosporine 100 mg single dose 800 mg three times daily x 7 days 2.01
(1.69-2.40)
2.68¶
(2.38-3.03)
N/A
Darunavir /Ritonavir 600 mg/100 mg two times daily x 22 days 800 mg three times daily x 6 days Darunavir: 0.64
(0.58-0.71) Ritonavir: 0.87
(0.76-1.00)
Darunavir: 0.56§
(0.51-0.61) Ritonavir: 0.73
(0.68-0.79)
Darunavir: 0.41
(0.38-0.45) Ritonavir: 0.55
(0.52-0.59)
Digoxin 0.25 mg single dose 800 mg three times daily x 10 days 1.18
(1.07-1.31)
1.19¶
(1.12-1.27)
N/A
Drospirenone/ Ethinyl estradiol Drospirenone: 3 mg + Ethinyl estradiol: 0.02 mg daily x 14 days 800 mg three times daily x 7 days Drospirenone: 1.57
(1.46-1.70) Ethinyl estradiol: 1.00
(0.91-1.10)
Drospirenone: 1.99
(1.87-2.11) Ethinyl estradiol: 0.76
(0.73-0.79)
N/A
Efavirenz 600 mg daily x 16 days 800 mg three times daily x 6 days 1.11
(1.02-1.20)
1.20
(1.15-1.26)
N/A
Escitalopram 10 mg single dose 800 mg three times daily x 11 days 0.81
(0.76-0.87)
0.79¶
(0.71-0.87)
N/A
Etravirine 200 mg two times daily x 1114 days 800 mg three times daily x 11-14 days 0.76
(0.68-0.85)
0.77
(0.66-0.91)
0.71
(0.54-0.95)
Lopinavir/ Ritonavir 400 mg/100 mg two times daily x 22 days 800 mg three times daily x 6 days Lopinavir: 0.70
(0.65-0.77) Ritonavir: 0.88
(0.72-1.07)
Lopinavir: 0.66§
(0.60-0.72) Ritonavir: 0.78
(0.71-0.87)
Lopinavir: 0.57
(0.49-0.65) Ritonavir: 0.58
(0.52-0.65)
Methadone 20-150 mg daily x 6 days 800 mg three times daily x 6 days R-methadone: 0.90
(0.71-1.13) S-methadone: 0.83
(0.64-1.09)
R-methadone: 0.85
(0.74-0.96) S-methadone: 0.78
(0.66-0.93)
R-methadone: 0.81
(0.66-1.00) S-methadone: 0.74
(0.58-0.95)
Midazolam 4 mg single oral dose 800 mg three times daily x 6 days 2.77
(2.36-3.25)
5.30
(4.66-6.03)
N/A
Norethindrone/ Ethinyl estradiol Norethindrone: 1 mg + Ethinyl estradiol : 0.035 mg daily x 21 days 800 mg three times daily x 28 days Norethindrone: 0.83
(0.76-0.90) Ethinyl estradiol: 0.79
(0.75 -0.84)
Norethindrone: 0.96
(0.87-1.06) Ethinyl estradiol: 0.74
(0.68-0.80)
N/A
Omeprazole 40 mg daily x 5 days 800 mg three times daily x 5 days 1.03
(0.85-1.26)
1.06
(0.90-1.25)
1.12 Þ
(0.75-1.67)
Peginterferonalfa-2b 1.5 mcg/kg subcutaneous weekly x 2 weeks 200 mg or 400 mg three times daily x 1 week N/A 0.99†,‡
(0.83-1.17)
N/A
Pravastatin 40 mg single dose 800 mg three times daily x 6 days 1.49
(1.03-2.14)
1.63¶
(1.01-2.62)
N/A
Prednisone 40 mg single dose 800 mg three times daily x 6 days Prednisone: 0.99
(0.94-1.04) Prednisolone: 1.16
(1.09-1.24)
Prednisone: 1.22
(1.16-1.28) Prednisolone: 1.37
(1.31-1.44)
Prednisone: N/A Prednisolone: N/A
Raltegravir 400 mg single dose 800 mg three times daily x 10 days 1.11
(0.91-1.36)
1.04
(0.88-1.22)
0.75#
(0.45-1.23)
Rilpivirine 25 mg every 24 hours x 11 days 800 mg three times daily x 11 days 1.15
(1.04, 1.28)
1.39§
(1.27, 1.52)
1.51
(1.36, 1.68)
Sirolimus 2 mg single dose 800 mg every 8 hours x 9 days 4.84
(3.99, 5.88)
8.12¶
(7.08, 9.32)
N/A
Tacrolimus 0.5 mg single dose 800 mg three times daily x 11 days 9.90
(7.96-12.3)
17.1¶
(14.0-20.8)
N/A
Tenofovir 300 mg daily x 7 days 800 mg three times daily x 7 days 1.32
(1.19-1.45)
1.05
(1.01-1.09)
N/A
*No effect = 1.00
†0-168 hours
‡Reported AUC is 200 mg and 400 mg cohorts combined.
§ AUC0- last
¶AUC0-inf
#C12 hours
Þ C8 hours
N/A = not available

Elimination

Boceprevir is eliminated with a mean plasma half-life (t½) of approximately 3.4 hours. Boceprevir has a mean total body clearance (CL/F) of approximately 161 L per hr. Following a single 800 mg oral dose of 14C-boceprevir, approximately 79% and 9% of the dose was excreted in feces and urine, respectively, with approximately 8% and 3% of the dosed radiocarbon eliminated as boceprevir in feces and urine. The data indicate that boceprevir is eliminated primarily by the liver.

Special Populations

Hepatic Impairment

The pharmacokinetics of boceprevir was studied in adult non-HCV infected subjects with normal, mild (Child-Pugh score 5 to 6), moderate (Child-Pugh score 7 to 9), and severe (Child-Pugh score 10 to 12) hepatic impairment following a single 400 mg dose of VICTRELIS. The mean AUC of the active diastereomer of boceprevir (SCH534128) was 32% and 45% higher in subjects with moderate and severe hepatic impairment, respectively, relative to subjects with normal hepatic function. Mean Cmax values for SCH534128 were 28% and 62% higher in moderate and severe hepatic impairment, respectively. Subjects with mild hepatic impairment had similar SCH534128 exposure as subjects with normal hepatic function. A similar magnitude of effect is anticipated for boceprevir. No dosage adjustment of VICTRELIS is recommended for patients with hepatic impairment [see Use in Specific Populations]. See peginterferon alfa Package Insert for contraindication in patients with hepatic decompensation.

Renal Impairment

The pharmacokinetics of boceprevir was studied in non-HCV-infected subjects with end-stage renal disease (ESRD) requiring hemodialysis following a single 800 mg dose of VICTRELIS. The mean AUC of boceprevir was 10% lower in subjects with ESRD requiring hemodialysis relative to subjects with normal renal function. Hemodialysis removed less than 1% of the boceprevir dose. No dosage adjustment of VICTRELIS is required in patients with any degree of renal impairment.

Gender

Population pharmacokinetic analysis of VICTRELIS indicated that gender had no apparent effect on exposure.

Race

Population pharmacokinetic analysis of VICTRELIS indicated that race had no apparent effect on exposure.

Age

Population pharmacokinetic analysis of VICTRELIS showed that boceprevir exposure was not different across subjects 19 to 65 years old.

Microbiology

Mechanism of Action

Boceprevir is an inhibitor of the HCV NS3/4A protease that is necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins. Boceprevir covalently, yet reversibly, binds to the NS3 protease active site serine (S139) through an (alpha)-ketoamide functional group to inhibit viral replication in HCV-infected host cells. In a biochemical assay, boceprevir inhibited the activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes, with Ki values of 14 nM for each subtype.

Activity in Cell Culture

The EC50 and EC90 values for boceprevir against an HCV replicon constructed from a single genotype 1b isolate were approximately 200 nM and 400 nM, respectively, in a 72-hour cell culture assay. Boceprevir cell culture anti-HCV activity was approximately 2-fold lower for an HCV replicon derived from a single genotype 1a isolate, relative to the 1b isolate-derived replicon. In replicon assays, boceprevir had approximately 2-fold reduced activity against a genotype 2a isolate relative to genotype 1a and 1b replicon isolates. In a biochemical assay, boceprevir had approximately 3-and 2-fold reduced activity against NS3/4A proteases derived from single isolates representative of HCV genotypes 2 and 3a, respectively, relative to a genotype 1b-derived NS3/4A protease. The presence of 50% human serum reduced the cell culture anti-HCV activity of boceprevir by approximately 3-fold.

Evaluation of varying combinations of boceprevir and interferon alfa-2b that produced 90% suppression of replicon RNA in cell culture showed additivity of effect without evidence of antagonism.

Resistance

In HCV Replicon Cell Culture and Biochemical Studies

The activity of boceprevir against the HCV genotype 1a replicon was reduced (2-to 6-fold) by the following amino acid substitutions in the NS3 protease domain: V36A/L/M, Q41R, T54A/S, V55A, R155K and V158I. A greater than 10-fold reduction in boceprevir susceptibility was conferred by the amino acid substitutions R155T and A156S. The V55I and D168N single substitutions did not reduce sensitivity to boceprevir. The following double amino acid substitutions conferred more than 10-fold reduced sensitivity to boceprevir: V55A+I170V, T54S+R155K, R155K+D168N, R155T+D168N and V36M+R155K.

The activity of boceprevir against the HCV genotype 1b replicon was reduced (2-to 8-fold) by the following amino acid substitutions in the NS3 protease domain: V36A/M, Q41R, F43S, T54A/G/S, V55A/I, R155K, V158I, V170M and M175L. A greater than 10-fold reduction in boceprevir susceptibility was conferred by the amino acid substitutions A156S/T/V, V170A and V36M+R155K. The D168V single substitution did not reduce sensitivity to boceprevir.

Additional NS3 protease domain substitutions that have not been evaluated in the HCV replicon but have been shown to reduce boceprevir activity against the HCV NS3/4A protease in a biochemical assay include F43C and R155G/I/M/Q.

Resistance-associated amino acid substitutions for HCV genotype 1a and 1b observed in clinical trials are presented in Table 8.

In Clinical Studies

An as-treated, pooled genotypic resistance analysis was conducted for subjects who received four weeks of PegIntron/REBETOL followed by VICTRELIS 800 mg three times daily in combination with PegIntron/REBETOL in two Phase 3 studies, SPRINT-2 and RESPOND-2. Among subjects treated with VICTRELIS who did not achieve a sustained virologic response, and for whom samples were analyzed, 53% had one or more specific post-baseline, treatment-emergent NS3 protease domain amino acid substitutions detected by a population-based sequencing assay (Table 8). Similar patterns of treatment-emergent substitutions were observed in P06086, a Phase 3 clinical trial in previously untreated CHC subjects with genotype 1 infection comparing the use of ESA to ribavirin dose reduction for initial management of anemia during therapy with VICTRELIS in combination with PegIntron/REBETOL. Nearly all of these substitutions have been shown to reduce boceprevir anti-HCV activity in cell culture or biochemical assays. Among subjects treated with VICTRELIS in SPRINT-2 and RESPOND-2 who did not achieve SVR and for whom post-baseline samples were analyzed, 31% of PegIntron/REBETOLresponsive subjects, as defined by greater than or equal to 1-log10 decline in viral load at Treatment W eek 4 (end of 4-week PegIntron/REBETOL lead-in period), had detectable treatment-emergent substitutions, compared to 68% of subjects with less than 1-log10 decline in viral load at Treatment Week 4. Clear patterns of boceprevir treatment-emergent substitutions in the NS3 helicase domain or NS4A coding regions of the HCV genome were not observed.

Table 8 : Treatment-Emergent NS3 Protease Domain Amino Acid Substitutions Detected Among Subjects treated with VICTRELIS in SPRINT-2, RESPOND-2 and P06086 Who Did Not Achieve a Sustained Virologic Response (SVR)

  Subjects Infected with HCV Genotype 1a Subjects Infected with HCV Genotype 1b
> 10% of subjects treated with VICTRELIS who did not achieve SVR
V36M, T54S, R155K
T54A, T54S, V55A, A156S, V170A
< 1% to 10% of subjects treated with VICTRELIS who did not achieve SVR
V36A, T54A, V55A, V55I, V107I, R155T, A156S, A156T, V158I, D168N, I170F, I170T, I170V
V36A, V36M, T54C, T54G, V107I, R155C, R155K, A156T, A156V, V158I, I/V170T, M175L

Persistence of Resistance-Associated Substitutions

Data from an ongoing, long-term follow-up study of subjects who did not achieve SVR in Phase 2 trials with VICTRELIS, with a median duration of follow-up of approximately 2 years, indicate that HCV populations harboring certain post-baseline, treatment-emergent substitutions may decline in relative abundance over time. However, among those subjects with available data, one or more treatment-emergent substitutions remained detectable with a population-based sequencing assay in 25% of subjects after 2.5 years of follow-up. The most common NS3 substitutions detected after 2.5 years of follow-up were T54S and R155K. The lack of detection of a substitution based on a population-based assay does not necessarily indicate that viral populations carrying that substitution have declined to a background level that may have existed prior to treatment. The long-term clinical impact of the emergence or persistence of boceprevir-resistance-associated substitutions is unknown. No data are available regarding the efficacy of VICTRELIS among subjects who were previously exposed to VICTRELIS, or who previously failed treatment with a regimen containing VICTRELIS.

Effect of Baseline HCV Polymorphisms on Treatment Response

A pooled analysis was conducted to explore the association between the detection of baseline NS3/4A amino acid polymorphisms and treatment outcome in the two Phase 3 studies, SPRINT-2 and RESPOND-2.

Baseline resistance associated polymorphisms were detected in 7% of subjects by a population-based sequencing method. Overall, the presence of these polymorphisms alone did not impact SVR rates in subjects treated with VICTRELIS. However, among subjects with a relatively poor response to PegIntron/REBETOL during the 4-week lead-in period, the efficacy of VICTRELIS appeared to be reduced for those who had V36M, T54A, T54S, V55A or R155K detected at baseline. Subjects with these baseline polymorphisms and reduced response to PegIntron/REBETOL represented approximately 1% of the total number of subjects treated with VICTRELIS.

Cross-Resistance

Many of the treatment-emergent NS3 amino acid substitutions detected in subjects treated with VICTRELIS who did not achieve SVR in the Phase 3 clinical trials have been demonstrated to reduce the anti-HCV activity of other HCV NS3/4A protease inhibitors. The impact of prior exposure to VICTRELIS or treatment failure on the efficacy of other HCV NS3/4A protease inhibitors has not been studied. The efficacy of VICTRELIS has not been established for patients with a history of exposure to other NS3/4A protease inhibitors. Cross-resistance is not expected between VICTRELIS and interferons, or VICTRELIS and ribavirin.

Pharmacogenomics

A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C to T change) is a strong predictor of response to PegIntron/REBETOL. IL28B rs12979860 was genotyped in 653 of 1048 (62%) subjects in SPRINT-2 (previously untreated) and 259 of 394 (66%) subjects in RESPOND-2 (previous partial responders and relapsers) [see Clinical Studies for trial descriptions]. Among subjects that received at least one dose of placebo or VICTRELIS (Modified-Intent-to-Treat population), SVR rates tended to be lower in subjects with the C/T and T/T genotypes compared to those with the C/C genotype, particularly among previously untreated subjects receiving 48 weeks of PegIntron and REBETOL (see Table 9). Among previous treatment failures, subjects of all genotypes appeared to have higher SVR rates with regimens containing VICTRELIS. The results of this retrospective subgroup analysis should be viewed with caution because of the small sample size and potential differences in demographic or clinical characteristics of the substudy population relative to the overall trial population.

Table 9 : Sustained Virologic Response (SVR) Rates by IL28B rs12979860 Genotype

Clinical Study IL28B rs12979860 Genotype SVR, % (n/N)
PR48* Boceprevir-RGT* Boceprevir-PR48*
SPRINT-2 (Previously Untreated Subjects)
  C/C 78 (50/64) 82 (63/77) 80 (44/55)
  C/T 28 (33/116) 65 (67/103) 71 (82/115)
  T/T 27 (10/37) 55 (23/42) 59 (26/44)
RESPOND-2 (Previous Partial Responders and Relapsers)
  C/C 46 (6/13) 79 (22/28) 77 (17/22)
  C/T 17 (5/29) 61 (38/62) 73 (48/66)
  T/T 50 (5/10) 55 (6/11) 72 (13/18)
*For description of each treatment arm, see Clinical Studies.

Clinical Studies

The efficacy of VICTRELIS as a treatment for chronic hepatitis C (genotype 1) infection was assessed in approximately 1500 adult subjects who were previously untreated (SPRINT-2) or who had failed previous peginterferon alfa and ribavirin therapy (RESPOND-2) in Phase 3 clinical studies.

Previously Untreated Subjects

SPRINT-2 was a randomized, double-blind, placebo-controlled study comparing two therapeutic regimens of VICTRELIS 800 mg orally three times daily in combination with PR [PegIntron 1.5 micrograms per kg per week subcutaneously and weight-based dosing with REBETOL (600-1400 mg per day orally divided twice daily)] to PR alone in adult subjects who had chronic hepatitis C (HCV genotype 1) infection with detectable levels of HCV-RNA and were not previously treated with interferon alfa therapy. Subjects were randomized in a 1:1:1 ratio within two separate cohorts (Cohort 1/non-Black and Cohort 2/Black) and were stratified by HCV genotype (1a or 1b) and by HCV-RNA viral load (less than or equal to 400,000 IU per mL vs. more than 400,000 IU per mL) to one of the following three treatment arms:

  • PegIntron + REBETOL for 48 weeks (PR48).
  • PegIntron + REBETOL for four weeks followed by VICTRELIS 800 mg three times daily + PegIntron + REBETOL for 24 weeks. The subjects were then continued on different regimens based on Treatment Week (TW) 8 through TW24 response-guided therapy (boceprevir-RGT). All subjects in this treatment arm were limited to 24 weeks of therapy with VICTRELIS.
    • Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and remained undetectable through TW24 discontinued therapy and entered follow-up at the TW28 visit.
    • Subjects with detectable HCV-RNA at TW8 or any subsequent treatment week but subsequently achieving undetectable HCV-RNA (Target Not Detected) at TW24 (late responders) were changed in a blinded fashion to placebo at the TW28 visit and continued therapy with PegIntron + REBETOL for an additional 20 weeks, for a total treatment duration of 48 weeks.
  • PegIntron + REBETOL for four weeks followed by VICTRELIS 800 mg three times daily + PegIntron + REBETOL for 44 weeks (boceprevir-PR48).

All subjects with detectable HCV-RNA in plasma at TW24 were discontinued from treatment. Sustained Virologic Response (SVR) was defined as plasma HCV-RNA less than 25 IU/mL at Follow-up Week 24. Plasma HCV-RNA results at Follow-up Week 12 were used if plasma HCV-RNA results at Follow-up Week 24 were missing.

Mean age of subjects randomized was 49 years. The racial distribution of subjects was as follows: 82% White, 14% Black, and 4% others. The distribution of subjects by gender was 60% men and 40% women.

The addition of VICTRELIS to PegIntron and REBETOL significantly increased the SVR rates compared to PegIntron and REBETOL alone in the combined cohort (63% to 66% in arms containing VICTRELIS vs. 38% PR48 control) for randomized subjects who received at least one dose of any study medication (Full-Analysis-Set population). SVR rates for Blacks who received the combination of VICTRELIS with PegIntron and REBETOL were 42% to 53% in a predefined analysis (see Table 10).

Table 10 : Sustained Virologic Response (SVR)*, † and Relapse Rates‡ for Previously Untreated Subjects

Study Cohorts Boceprevir-RGT Boceprevir-PR48 PR48
Cohort 1 Plus Cohort 2 (all subjects) n=368 n=366 n=363
SVR† % 63 66 38
Relapse‡ % 9 9 22
(n/N) (24/257) (24/265) (39/176)
Cohort 1 Plus Cohort 2 (subjects without cirrhosis)
SVR†,§ % (n/N) 65 (228/352) 68 (232/342) 38 (132/350)
Cohort 1 (non-Black) n=316 n=311 n=311
SVR† % 67 68 40
Relapse‡ % (n/N) 9 (21/232) 8 (18/230) 23 (37/162)
Cohort 2 (Black) n=52 n=55 n=52
SVR† % 42 53 23
Relapse‡ % (n/N) 12 (3/25) 17 (6/35) 14 (2/14)
*The Full Analysis Set (FAS) consisted of all randomized subjects (N=1097) who received at least one dose of any study medication (PegIntron, REBETOL, or VICTRELIS).
†Sustained Virologic Response (SVR): reported as plasma HCV-RNA < 25 IU/mL at follow-up week (FW) 24. The last available HCVRNA value in the period at or after FW24 was used. If HCV-RNA value at FW24 was missing, the FW12 value was carried forward.
‡Relapse rate was the proportion of subjects with undetectable HCV-RNA (Target Not Detected) at End of Treatment (EOT) and HCVRNA ≥ 25 IU/mL at End of Follow-up (EOF) among subjects who were undetectable at EOT and not missing End of Follow-up (EOF) data.
§ Includes subjects with missing baseline data regarding cirrhosis as diagnosed by liver biopsy.

In subjects with cirrhosis at baseline, sustained virologic response was higher in those who received treatment with the combination of VICTRELIS with PegIntron and REBETOL for 44 weeks after lead-in therapy with PegIntron and REBETOL (10/24, 42%) compared to those who received RGT (5/16 , 31%).

Sustained Virologic Response (SVR) Based on TW8 HCV-RNA Results

Table 11 presents sustained virologic response based on TW8 HCV-RNA results in previously untreated subjects. Fifty-seven percent (208/368) of subjects in the boceprevir-RGT arm and 56% (204/366) of subjects in the boceprevir-PR48 arm had undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) compared with 17% (60/363) of subjects in the PR48 arm.

Table 11 : Sustained Virologic Response (SVR) by HCV-RNA Detectability at TW8 in Previously Untreated Subjects in the Combined Cohort

  Boceprevir-RGT Boceprevir-PR48 PR48
SVR by TW8 Detectability, % (n/N)* N=337 N=335 N=331
Undetectable (Target Not Detected) 88 (184/208) 90 (184/204) 85 (51/60)
Detectable 36 (46/129) 40 (52/131) 30 (82/271)
*Denominator included only subjects with HCV-RNA results at TW8.

Among subjects with detectable HCV-RNA at TW8 who had attained undetectable HCV-RNA (Target Not Detected) at TW24 and completed at least 28 weeks of treatment, the SVR rates were 66% (45/68) in boceprevir-RGT arm (4 weeks of PegIntron and REBETOL then 24 weeks of VICTRELIS with PegIntron and REBETOL followed by 20 weeks of PegIntron and REBETOL alone) and 75% (55/73) in boceprevirPR48 arms (4 weeks of PegIntron and REBETOL then 44 weeks of VICTRELIS with PegIntron and REBETOL).

Previous Partial Responders and Relapsers to Interferon and Ribavirin Therapy

RESPOND-2 was a randomized, parallel-group, double-blind study comparing two therapeutic regimens of VICTRELIS 800 mg orally three times daily in combination with PR [PegIntron 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600-1400 mg per day orally divided twice daily)] compared to PR alone in adult subjects with chronic hepatitis C (HCV genotype 1) infection with demonstrated interferon responsiveness (as defined historically by a decrease in HCV-RNA viral load greater than or equal to 2-log10 by W eek 12, but never achieved SVR [partial responders] or undetectable HCV-RNA at end of prior treatment with a subsequent detectable HCV-RNA in plasma [relapsers]). Subjects with less than 2-log10 decrease in HCV-RNA by week 12 of previous treatment (prior null responders) were not eligible for enrollment in this trial. Subjects were randomized in a 1:2:2 ratio and stratified based on response to their previous qualifying regimen (relapsers vs. partial responders) and by HCV subtype (1a vs. 1b) to one of the following treatment arms:

  • PegIntron + REBETOL for 48 weeks (PR48)
  • PegIntron + REBETOL for 4 weeks followed by VICTRELIS 800 mg three times daily + PegIntron + REBETOL for 32 weeks. The subjects were then continued on different treatment regimens based on TW8 and TW12 response-guided therapy (boceprevir-RGT). All subjects in this treatment arm were limited to 32 weeks of VICTRELIS.
    • Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and TW12 completed therapy at TW36 visit.
    • Subjects with a detectable HCV-RNA at TW8 but subsequently undetectable (Target Not Detected) at TW12 (late responders) were changed in a blinded fashion to placebo at the TW36 visit and continued treatment with PegIntron + REBETOL for an additional 12 weeks, for a total treatment duration of 48 weeks.
  • PegIntron + REBETOL for 4 weeks followed by VICTRELIS 800 mg three times daily + PegIntron + REBETOL for 44 weeks (boceprevir-PR48).

All subjects with detectable HCV-RNA in plasma at TW12 were discontinued from treatment. Sustained Virologic Response (SVR) was defined as plasma HCV-RNA less than 25 IU/mL at Follow-up Week 24. Plasma HCV-RNA results at Follow-up Week 12 were used if plasma HCV-RNA results at Follow-up Week 24 were missing.

Mean age of subjects randomized was 53 years. The racial distribution of subjects was as follows: 85% White, 12% Black, and 3% others. The distribution of subjects by gender was 67% men and 33% women.

The addition of VICTRELIS to the PegIntron and REBETOL therapy significantly increased the SVR rates compared to PegIntron/REBETOL alone (59% to 66% in arms containing VICTRELIS vs. 23% PR48 control) for randomized subjects who received at least one dose of any study medication (FullAnalysis-Set population) (see Table 12).

Table 12 : Sustained Virologic Response (SVR)*, † and Relapse‡ Rates for Subjects Who have Failed Previous Therapy with Peginterferon Alfa and Ribavirin (Previous Partial Responders and Relapsers)

  Boceprevir-RGT
N=162
Boceprevir-PR48
N=161
PR48
N=80
SVR† % 59 66 23
Relapse‡ % (n/N) 14 (16/111) 12 (14/121) 28 (7/25)
SVR (subjects without cirrhosis) § (n/N) 62 (90/145) 65 (90/139) 26 (18/70)
SVR by Response to Previous Peginterferon and Ribavirin Therapy
Previous Response Relapser, % (n/N) 70 (73/105) 75 (77/103) 31 (16/51)
Partial responder, % (n/N) 40 (23/57) 52 (30/58) 7 (2/29)
*The Full Analysis Set (FAS) consisted of all randomized subjects (N=403) who received at least one dose of any study medication (PegIntron, REBETOL, or VICTRELIS).
†Sustained Virologic Response (SVR): reported as plasma HCV-RNA < 25 IU/mL at follow-up week (FW) 24. The last available HCV-RNA value in the period at or after FW24 was used. If HCV-RNA value at FW24 was missing, the FW12 value was carried forward.
‡Relapse rate was the proportion of subjects with undetectable HCV-RNA (Target Not Detected) at End of Treatment (EOT) and HCV-RNA ≥ 25 IU/mL at End of Follow-up (EOF) among subjects who were undetectable at EOT and not missing End of Follow-up (EOF) data.
§ Includes subjects with missing baseline data regarding cirrhosis as diagnosed by liver biopsy.
Previous Partial Responder = subject who failed to achieve SVR after at least 12 weeks of previous treatment with peginterferon alfa and ribavirin, but demonstrated a ≥ 2-log10 reduction in HCV-RNA by Week 12.
Previous Relapser = subject who failed to achieve SVR after at least 12 weeks of previous treatment with peginterferon alfa and ribavirin, but had undetectable HCV-RNA at the end of treatment.

In subjects with cirrhosis at baseline, sustained virologic response was higher in those who received treatment with the combination of VICTRELIS with PegIntron and REBETOL for 44 weeks after 4 weeks of lead-in therapy with PegIntron and REBETOL (17/22, 77%) compared to those who received RGT (6/17, 35%).

Sustained Virologic Response (SVR) Based on TW8 HCV-RNA Results

Table 13 presents sustained virologic response based on TW8 HCV-RNA results in subjects who were relapsers or partial responders to previous interferon and ribavirin therapy. Forty-six percent (74/162) of subjects in the boceprevir-RGT arm and 52% (84/161) in the boceprevir-PR48 had undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) compared with 9% (7/80) in the PR48 arm.

Table 13 : Sustained Virologic Response (SVR) by HCV-RNA Detectability at TW8 in Subjects Who Have Failed Previous Therapy (Previous Partial Responders and Relapsers)

SVR by TW8 Detectability, % (n/N)* Boceprevir-RGT
N=146
Boceprevir-PR48
N=154
PR48
N=72
Undetectable (Target Not Detected) 88 (65/74) 88 (74/84) 100 (7/7)
Detectable 40 (29/72) 43 (30/70) 14 (9/65)
*Denominator included only subjects with HCV-RNA results at TW8.

Among subjects with detectable HCV-RNA at TW8 who attained an undetectable HCV-RNA (Target Not Detected) at TW12 and completed at least 36 weeks of treatment, the SVR rates were 79% (27/34) in boceprevir-RGT arm (4 weeks of PegIntron and REBETOL then 32 weeks of VICTRELIS with PegIntron and REBETOL followed by 12 weeks of PegIntron and REBETOL alone) and 72% (29/40) in boceprevirPR48 arm (4 weeks of PegIntron and REBETOL then 44 weeks of VICTRELIS with PegIntron and REBETOL).

Interferon Responsiveness during Lead-In Therapy with Peginterferon alfa and Ribavirin

Previously Untreated Subjects

In previously untreated subjects evaluated in SPRINT-2, interferon-responsiveness (defined as greater than or equal to 1-log10 decline in viral load at TW4) was predictive of SVR. Subjects treated with VICTRELIS who demonstrated interferon responsiveness at TW4 achieved SVR rates of 81% (203/252) in boceprevir-RGT arm and 79% (200/254) in boceprevir-PR48 arm, compared to 52% (134/260) in subjects treated with PegIntron/REBETOL.

Subjects treated with VICTRELIS who demonstrated poor interferon responsiveness (defined as less than 1-log10 decline in viral load at TW4), achieved SVR rates of 28% (27/97) in boceprevir-RGT arm and 38% (36/95) in boceprevir-PR48 arm, compared to 4% (3/83) in subjects treated with PegIntron/REBETOL. Subjects with less than a 0.5-log10 decline in viral load at TW4 achieved SVR rates of 28% (13/47) in boceprevir-RGT arm and 30% (11/37) in boceprevir-PR48 arm, compared to 0% (0/25) in subjects treated with PegIntron/REBETOL. Subjects with less than a 0.5-log10 decline in viral load at TW4 with peginterferon alfa plus ribavirin therapy alone are predicted to have a null response (less than 2-log10 viral load decline at TW12) to peginterferon alfa and ribavirin.

Previous Partial Responders and Relapsers to Interferon and Ribavirin Therapy

In subjects who were previous relapsers and partial responders evaluated in RESPOND-2, interferon-responsiveness (defined as greater than or equal to 1-log10 decline in viral load at TW4) was predictive of SVR. Subjects treated with VICTRELIS who demonstrated interferon responsiveness at TW4 achieved SVR rates of 74% (81/110) in boceprevir-RGT arm and 79% (90/114) in boceprevir-PR48 arm, compared to 27% (18/67) in subjects treated with PegIntron/REBETOL. Subjects treated with VICTRELIS who demonstrated poor interferon responsiveness (defined as less than 1-log10 decline in viral load at TW4) achieved SVR rates of 33% (15/46) in boceprevir-RGT arm and 34% (15/44) in boceprevir-PR48 arm, compared to 0% (0/12) in subjects treated with PegIntron/REBETOL.

Prior Null Responders to Interferon and Ribavirin Therapy

PROVIDE is an ongoing, open-label, single-arm study of VICTRELIS 800 mg orally three times daily in combination with peginterferon alfa-2b 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600 - 1,400 mg per day orally divided twice daily) in adult subjects with chronic hepatitis C (HCV) genotype 1 infection who did not achieve SVR while in the peginterferon alfa/ribavirin control arms of previous Phase 2 and 3 studies of combination therapy with VICTRELIS. Subjects who enrolled in PROVIDE within 2 weeks after the last dose of peginterferon alfa/ribavirin in the parent study received VICTRELIS 800 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks. Subjects who were not able to enroll in this study within 2 weeks received PegIntron/REBETOL lead-in for 4 weeks followed by VICTRELIS 800 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks.

Among the subjects who were null responders in the peginterferon alfa/ribavirin control arm of the parent study that received the 4-week PegIntron/REBETOL lead-in treatment followed by VICTRELIS 800 mg three times daily + PegIntron/REBETOL for 44 weeks, 38% (20/52) achieved SVR, and the relapse rate was 14% (3/22).

Use of Ribavirin Dose Reduction versus Erythropoiesis Stimulating Agent (ESA) in the Management of Anemia in Previously Untreated Subjects

A randomized, parallel-arm, open-label study was conducted to compare two strategies for the management of anemia (use of ESA versus ribavirin dose reduction) in 687 subjects with previously untreated CHC genotype 1 infection who became anemic during therapy with VICTRELIS 800 mg orally three times daily plus peginterferon alfa-2b 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600 - 1,400 mg orally per day divided twice daily). The study enrolled subjects with serum hemoglobin concentrations of less than 15 g per dL. Subjects were treated for 4 weeks with peginterferon alfa-2b and ribavirin followed by up to 44 weeks of VICTRELIS plus peginterferon alfa-2b and ribavirin. If a subject became anemic (serum hemoglobin of approximately less than or equal to 10 g per dL within the treatment period), the subject was randomized in a 1:1 ratio to either ribavirin dose reduction (N=249) or use of erythropoietin 40,000 units subcutaneously once weekly for the management of the anemia (N=251). If serum hemoglobin concentrations continued to decrease to less than or equal to 8.5 g per dL, subjects could be treated with additional anemia interventions, including the addition of erythropoietin (18% of those in the ribavirin dose reduction arm) or ribavirin dose reduction (37% of those in the ESA arm).

Mean age of subjects randomized was 49 years. The racial distribution of subjects was as follows: 77% W hite, 19% Black, and 4% other. The distribution of subjects by gender was 37% men and 63% women.

The overall intent-to-treat SVR rate for all enrolled subjects (including those subjects who were not randomized to RBV dose reduction or ESA for the management of anemia) was 63% (431/687). The SVR rate in subjects randomized who received ribavirin dose reduction was 71% (178/249), similar to the SVR rate of 71% (178/251) in subjects randomized to receive an ESA. The relapse rates in subjects randomized to receive ribavirin dose reduction or an ESA were 10% (19/196) and 10% (19/197), respectively.

Last reviewed on RxList: 2/21/2014
This monograph has been modified to include the generic and brand name in many instances.

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