Pharmacology Update

Boceprevir Capsules (Victrelis™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

The FDA has approved Boceprevir, a protease inhibitor for the treatment of chronic hepatitis C (HCV) infections. Boceprevir is an inhibitor of HCV non-structural protein 3 (NS3) serine protease. It is marketed by Merck & Co. as Victrelis. Boceprevir is the first of several protease inhibitors expected to be approved for this indication in the near future.

Indications

Boceprevir is indicated for the treatment of chronic HCV genotype 1 infections in adult patients with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.1

Dosage

The recommended dose is 800 mg (4 capsules) taken orally three times daily (every 7 to 9 hours) with food since food increases the absorption of boceprevir. It is taken concomitantly with peginterferon alfa-2b (1.5 mcg/kg weekly) and ribavirin (600 mg to 1400 mg per day based on weight).1 Dosing schedules for the different subgroups are as follows:

1. Patients without cirrhosis.

Start with peginterferon/ribavirin for 4 weeks then add boceprevir for 24 weeks. Subsequent therapy is based on response. For those who have undetectable virus at week 8 and 24, treatment is completed at week 28. For those in whom virus is detectable at week 8, but undetectable at week 24, continue boceprevir through week 36 and peginterferon/ribavirin through week 48 (B0C/RGT).

2. Patients previously untreated or who are previous partial responders or relapsers to interferon and ribavirin.

Start with peginterferon/ribavirin for 4 weeks then add boceprevir for 32 weeks. For those who have undetectable virus at week 8 and 24 treatment is completed at week 36. For those who have detectable virus at week 8, but undetectable virus at week 24, continue boceprevir through week 36 and then peginterferon/ribavirin through week 48.

3. Patients with cirrohsis — peginterferon/ribavirin for 4 weeks and boceprevir/peginterferone/ribavirin for 44 weeks (BOC/PR48).

Treatment should be discontinued if HCV-RNA levels are greater than or equal to 100 IU/mL at treatment week (TW) 12 or detectable at TW 24.

Boceprevir is available as 200 mg capsules.

Potential Advantages

The addition of boceprevir to standard therapy (peginterferon/ribavirin) significantly increased the rates of sustained virologic response in both treatment naïve and previously treated patients with chronic HCV genotype 1 infection.1-3

Potential Disadvantages

The most common adverse events associated with boceprevir (compared to peginterfon/ribavirin) were anemia (45%-50% vs 20%-30%) and dysgeusia (35%-44% vs 11%-16%).1 Treatment emergent virus in patents who have not achieved sustained viral response may be cross resistant to HCV NS3/4A protease inhibitors. Potent CYP3A4/5 inducers as well as drugs that are metabolized by the isoenzymes should be avoided. Treatment requires a high pill burden — 12 capsules per day — and a long and complex dosing schedule.

Comments

The efficacy and safety of boceprevir was evaluated in two randomized, double-blind trials, one in previously untreated patients (SPRINT-2) and the other in patients who had previously failed peginterferone/ribavirin (RESPOND-2). In SPRINT-2, patients with HCV RNA levels of 10,000 IU/mL or greater (n = 1097) were started on peginterferon alfa-2b (1.5 mcg/kg once weekly) and weight-based oral ribavirin (600 mg to 1400 mg/daily) for 4 weeks. One arm received boceprevir (800 mg three times daily) plus peginterferone/ribavirin for 24 weeks and they were followed by response-guided therapy (BOC/RGT). The second arm received boceprevir and peginterferon/ribavirn for 44 weeks (BOC/PR48). The third or control arm received placebo and peginterferon/ribavirin for 48 weeks (PR48). In response-guided therapy, those with undetectable virus at week 8-24 discontinued therapy and those detectable at week 8, but not week 24, received an additional 20 weeks of placebo plus peginterferon/ribavirin. Black patients and nonblack patients were enrolled separately into two cohorts. Each arm had a minimum follow-up of 24 weeks. The primary endpoint was sustained virologic response (SVR) defined as undetectable HCV-RNA at follow-up week 24 or week 12 if results were missing at week 24. SVR rates were 63% for BOC/RGT, 66% for BOCV/PR48, and 38% for the control arm. SVR for blacks were 42%, 53%, and 23% compared to 67%, 68%, and 40%, respectively for nonblacks (P < 0.05).2 Patients with cirrhosis and those with detectable virus at week 8 responded better with BOC/PR48 compared to BOC/RGT. Boceprevir-resistant variants were found in patents who achieved < 1 log10 decrease in HCV-RNA (47% for BOC/RGT and 35% for BOC/PR48). In RESPOND-2, patients who were noresponders or had relapsed were randomized to similar regimens except the BOC/RGT regimen was 32 weeks. SVR rates were 21% for control, 59% BOC/RGT, and 66% for BOC/PR48. Those who relapsed responded better than nonresponders (69% for BOC/RGT and 75% for BOC/PR48 compared to 40% and 52%, respectively). Similar to SPRINT-2, boceprevir-resistant variants were found in patients who did not respond as well. Anemia and dysgeusia were more common in the boceprevir group. Erythropoietin was given in approximately 40% of the cases of anemia. Common adverse events associated with triple therapy were fatigue, headache, and nausea.

Clinical Implications

Chronic HCV genotype 1 infections are the least responsive to pharmacotherapy. SVR with standard therapy (peginterferon/ribavirin) is around 40%.4 Boceprevir provides an important addition to the treatment of chronic HCV genotype 1 with significant improvement in SVR rates. Peginterferon/ribavirin will likely remain the treatment option for other genotypes at this time. Telaprevir, another protease inhibitor recently approved for the same indication, will be reviewed in the next issue of Internal Medicine Alert.

References

1. Victrelis Prescribing Information. Whitehouse Station, NJ: Merck & Co.; May 2011.

2. Poordad F, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195-1206.

3. Bacon BR, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1207-1217.

4. McHutchison JG, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580-593.