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Mechanism of Action

Pegylated recombinant human interferon alfa-2b is an inducer of the innate antiviral immune response.

Pharmacodynamics

The pharmacodynamic effects of peginterferon alfa-2b include inhibition of viral replication in virus-infected cells, the suppression of cell cycle progression/cell proliferation, induction of apoptosis, anti-angiogenic activities, and numerous immunomodulating activities, such as enhancement of the phagocytic activity of macrophages, activation of NK cells, stimulation of cytotoxic T-lymphocytes, and the upregulation of the Th1 T-helper cell subset.

PegIntron (peginterferon alfa-2b) raises concentrations of effector proteins such as serum neopterin and 2'5' oligoadenylate synthetase, raises body temperature, and causes reversible decreases in leukocyte and platelet counts. The correlation between the in vitro and in vivo pharmacologic and pharmacodynamic and clinical effects is unknown.

Pharmacokinetics

Following a single subcutaneous dose of PegIntron (peginterferon alfa-2b) , the mean absorption half-life (t ½ ka) was 4.6 hours. Maximal serum concentrations (Cmax) occur between 15 and 44 hours post dose, and are sustained for up to 48 to 72 hours. The Cmax and AUC measurements of PegIntron (peginterferon alfa-2b) increase in a dose-related manner. After multiple dosing, there is an increase in bioavailability of PegIntron (peginterferon alfa-2b) . Week 48mean trough concentrations (320 pg/mL; range: 0, 2960) are approximately 3-fold higher than Week 4 mean trough concentrations (94 pg/mL; range: 0, 416). The mean PegIntron (peginterferon alfa-2b) elimination half-life is approximately 40 hours (range: 22-60 hours) in patients with HCV infection. The apparent clearance of PegIntron (peginterferon alfa-2b) is estimated to be approximately 22mL/hr·kg. Renal elimination accounts for 30%of the clearance.

Pegylation of interferon alfa-2b produces a product (PegIntron (peginterferon alfa-2b) ) whose clearance is lower than that of nonpegylated interferon alfa-2b. When compared to INTRON A, PegIntron (peginterferon alfa-2b) (1 mcg/kg) has approximately a 7-fold lower mean apparent clearance and a 5-fold greater mean half-life, permitting a reduced dosing frequency. At effective therapeutic doses, PegIntron (peginterferon alfa-2b) has approximately 10-fold greater Cmax and 50-fold greater AUC than interferon alfa-2b.

Renal Dysfunction

Following multiple dosing of PegIntron (peginterferon alfa-2b) (1 mcg/kg subcutaneously given every week for 4 weeks) the clearance of PegIntron (peginterferon alfa-2b) is reduced by a mean of 17% in subjects with moderate renal impairment (creatinine clearance 30-49 mL/min) and by a mean of 44% in subjects with severe renal impairment (creatinine clearance 10-29 mL/min) compared to subjects with normal renal function. Clearance was similar in subjects with severe renal impairment not on dialysis and subjects who are receiving hemodialysis. The dose of PegIntron (peginterferon alfa-2b) for monotherapy should be reduced in patients with moderate or severe renal impairment [see DOSAGE AND ADMINISTRATION and REBETOL Package Insert]. REBETOL should not be used in patients with creatinine clearance < 50 mL/min [see REBETOL Package Insert, WARNINGS].

Gender

During the 48-week treatment period with PegIntron (peginterferon alfa-2b) , no differences in the pharmacokinetic profiles were observed between male and female subjects with chronic hepatitis C infection.

Geriatric Patients

The pharmacokinetics of geriatric subjects ( > 65 years of age) treated with a single subcutaneous dose of 1 mcg/kg of PegIntron (peginterferon alfa-2b) were similar in Cmax, AUC, clearance, or elimination half-life as compared to younger subjects (28-44 years of age).

Pediatric Patients

Population pharmacokinetics for PegIntron (peginterferon alfa-2b) and REBETOL (Capsules and Oral Solution) were evaluated in pediatric subjects with chronic hepatitis C between 3 and 17 years of age. In pediatric patients receiving PegIntron (peginterferon alfa-2b) 60 mcg/m²/week subcutaneously, exposure may be approximately 50% higher than observed in adults receiving 1.5 mcg/kg/week subcutaneously. The pharmacokinetics of REBETOL (dose-normalized) in this trial were similar to those reported in a prior study of REBETOL in combination with INTRON A in pediatric subjects and in adult subjects.

Effect of Food on Absorption of Ribavirin

Both AUC_tf and Cmax increased by 70% when REBETOL Capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study [see DOSAGE AND ADMINISTRATION].

Drug Interactions

Drugs Metabolized by Cytochrome P-450: The pharmacokinetics of representative drugs metabolized by CYP1A2 (caffeine), CYP2C8/9 (tolbutamide), CYP2D6 (dextromethorphan), CYP3A4 (midazolam), and N-acetyltransferase (dapsone) were studied in 22 subjects with chronic hepatitis C who received PegIntron (peginterferon alfa-2b) (1.5 mcg/kg) once weekly for 4 weeks. PegIntron (peginterferon alfa-2b) treatment resulted in a 28% (mean) increase in a measure of CYP2C8/9 activity. PegIntron (peginterferon alfa-2b) treatment also resulted in a 66%(mean) increase in a measure of CYP2D6 activity; however, the effect was variable as 13 subjects had an increase, 5 subjects had a decrease, and 4 subjects had no significant change [see DRUG INTERACTIONS].

No significant effect was observed on the pharmacokinetics of representative drugs metabolized by CYP1A2, CYP3A4, or N-acetyltransferase. The effects of PegIntron (peginterferon alfa-2b) on CYP2C19 activity were not assessed.

Methadone

The pharmacokinetics of concomitant administration of methadone and PegIntron (peginterferon alfa-2b) were evaluated in 18 PegIntron (peginterferon alfa-2b) -naïve chronic hepatitis C subjects receiving 1.5mcg/kg PegIntron (peginterferon alfa-2b) subcutaneously weekly. All subjects were on stable methadone maintenance therapy receiving > 40mg/day prior to initiating PegIntron (peginterferon alfa-2b) . Mean methadone AUC was approximately 16% higher after 4 weeks of PegIntron (peginterferon alfa-2b) treatment as compared to baseline. In 2 subjects, methadone AUC was approximately double after 4 weeks of PegIntron (peginterferon alfa-2b) treatment as compared to baseline [see DRUG INTERACTIONS] .

Use with Ribavirin

Zidovudine, Lamivudine, and Stavudine: Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine, lamivudine, and stavudine. However, in a study with another pegylated interferon in combination with ribavirin, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of amulti-drug regimen to HIV/HCV coinfected subjects [see DRUG INTERACTIONS] .

Didanosine

Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities [see DRUG INTERACTIONS] .

Microbiology

Mechanism of Action

The biological activity of PegIntron is derived from its interferon alfa-2b moiety. Peginterferon alfa-2b binds to and activates the human type 1 interferon receptor. Upon binding, the receptor subunits dimerize, and activate multiple intracellular signal transduction pathways. Signal transduction is initially mediated by the JAK/STAT activation, which may occur in a wide variety of cells. Interferon receptor activation also activates NFκB inmany cell types. Given the diversity of cell types that respond to interferon alfa-2b, and the multiplicity of potential intracellular responses to interferon receptor activation, peginterferon alfa-2b is expected to have pleiotropic biological effects in the body.

The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. Ribavirin increases the mutation frequency in the genomes of several viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.

Antiviral Activity

The anti-HCV activity of interferon was demonstrated in cell culture using selfreplicating HCV RNA (HCV replicon cells) or HCV infection and resulted in an effective concentration (EC₅₀) value of 1 to 10 IU/mL.

The antiviral activity of ribavirin in the HCV-replicon is not well understood and has not been defined because of the cellular toxicity of ribavirin.

Resistance

HCV genotypes show wide variability in their response to pegylated recombinant human interferon/ribavirin therapy. Genetic changes associated with the variable response have not been identified.

Cross-resistance

There is no reported cross-resistance between pegylated/nonpegylated interferons and ribavirin.

Clinical Studies

Chronic Hepatitis C in Adults

PegIntron (peginterferon alfa-2b) Monotherapy

Study 1: A randomized study compared treatment with PegIntron (peginterferon alfa-2b) (0.5, 1, or 1.5 mcg/kg once weekly subcutaneously) to treatment with INTRON A (3 million units 3 times weekly subcutaneously) in 1219 adults with chronic hepatitis from HCV infection. The subjects were not previously treated with interferon alpha, had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis. Subjects were treated for 48 weeks and were followed for 24 weeks posttreatment.

Seventy percent of all subjects were infected with HCV genotype 1, and 74 percent of all subjects had high baseline levels of HCV RNA (more than 2 million copies per mL of serum), 2 factors known to predict poor response to treatment.

Response to treatment was defined as undetectable HCV RNA and normalization of ALT at 24 weeks posttreatment. The response rates to the 1 and 1.5 mcg/kg PegIntron (peginterferon alfa-2b) doses were similar (approximately 24%) to each other and were both higher than the response rate to INTRON A (12%) (see Table 12).

TABLE 12: Rates of Response to Treatment – Study 1

Subjects with both viral genotype 1 and high serum levels of HCV RNA at baseline were less likely to respond to treatment with PegIntron (peginterferon alfa-2b) . Among subjects with the 2 unfavorable prognostic variables, 8% (12/157) responded to PegIntron (peginterferon alfa-2b) treatment and 2% (4/169) responded to INTRON A. Doses of PegIntron (peginterferon alfa-2b) higher than the recommended dose did not result in higher response rates in these subjects.

Subjects receiving PegIntron (peginterferon alfa-2b) with viral genotype 1 had a response rate of 14% (28/199) while subjects with other viral genotypes had a 45%(43/96) response rate.

Ninety-six percent of the responders in the PegIntron (peginterferon alfa-2b) groups and 100% of responders in the INTRON A group first cleared their viral RNA by Week 24 of treatment [see DOSAGE AND ADMINISTRATION].

The treatment response rates were similar in men and women. Response rates were lower in African-American and Hispanic subjects and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians, the number of non-Caucasians studied (9% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors.

Liver biopsies were obtained before and after treatment in 60%of subjects. Amodest reduction in inflammation compared to baseline that was similar in all 4 treatment groups was observed.

PegIntron (peginterferon alfa-2b) /REBETOL Combination Therapy

Study 2: A randomized study compared treatment with 2 PegIntron (peginterferon alfa-2b) /REBETOL regimens [PegIntron (peginterferon alfa-2b) 1.5 mcg/kg subcutaneously once weekly/REBETOL 800mg orally daily (in divided doses); PegIntron (peginterferon alfa-2b) 1.5mcg/kg subcutaneously once weekly for 4 weeks then 0.5mcg/kg subcutaneously once weekly for 44 weeks/REBETOL 1000 or 1200mg orally daily (in divided doses)] with INTRON A [3 MIU subcutaneously thrice weekly/REBETOL 1000 or 1200 mg orally daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon-naïve subjects were treated for 48 weeks and followed for 24 weeks posttreatment. Eligible subjects had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.

Response to treatment was defined as undetectable HCV RNA at 24 weeks posttreatment. The response rate to the PegIntron (peginterferon alfa-2b) 1.5mcg/kg plus ribavirin 800mg dosewas higher than the response rate to INTRON A/REBETOL (see Table13). The response rate to PegIntron (peginterferon alfa-2b) 1.5→0.5mcg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

TABLE 13: Rates of Response to Treatment – Study 2

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to PegIntron (peginterferon alfa-2b) (1.5mcg/kg)/REBETOL (800mg) compared to subjects with other viral genotypes. Subjects with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a response rate of 29%(71/247) with INTRON A/REBETOL.

Subjects with lower body weight tended to have higher adverse reaction rates [see ADVERSE REACTIONS] and higher response rates than subjects with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PegIntron (peginterferon alfa-2b) /REBETOL were 49% in men and 56% in women. Response rates were lower in African-American and Hispanic subjects and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians, the number of non-Caucasians studied (11%of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors in this study.

Liver biopsies were obtained before and after treatment in 68% of subjects. Compared to baseline, approximately two-thirds of subjects in all treatment groups were observed to have a modest reduction in inflammation.

PegIntron (peginterferon alfa-2b) /REBETOL Combination Therapy

Study 3: In a large United States community-based study (Study 3), 4913 subjects with chronic hepatitis C were randomized to receive PegIntron (peginterferon alfa-2b) 1.5 mcg/kg subcutaneously once weekly in combination with a REBETOL dose of 800 to 1400 mg (weight-based dosing [WBD]) or 800mg (flat) orally daily (in divided doses) for 24 or 48 weeks based on genotype. Response to treatment was defined as undetectable HCV RNA (based on an assay with a lower limit of detection of 125 IU/mL) at 24 weeks posttreatment.

Treatment with PegIntron (peginterferon alfa-2b) 1.5 mcg/kg and REBETOL 800 to 1400 mg resulted in a higher sustained virologic response compared to PegIntron (peginterferon alfa-2b) in combination with a flat 800 mg daily dose of REBETOL. Subjects weighing > 105 kg obtained the greatest benefit with WBD, although a modest benefit was also observed in subjects weighing > 85 to 105 kg (see Table 14). The benefit of WBD in subjects weighing > 85 kg was observed with HCV genotypes 1 through 3. Insufficient data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an increased incidence of anemia [see ADVERSE REACTIONS].

TABLE 14: SVR Rate by Treatment and Baseline Weight – Study 3

A total of 1552 subjects weighing > 65 kg in Study 3 had genotype 2 or 3 and were randomized to 24 or 48 weeks of therapy. No additional benefit was observed with the longer treatment duration.

PegIntron (peginterferon alfa-2b) /REBETOL Combination Therapy-Study 4

A large randomized study compared the safety and efficacy of treatment for 48 weeks with 2 PegIntron (peginterferon alfa-2b) /REBETOL regimens [PegIntron (peginterferon alfa-2b) 1.5 mcg/kg and 1 mcg/kg subcutaneously once weekly both in combination with REBETOL 800 to 1400 mg PO daily (in 2 divided doses)] and Pegasys 180 mcg subcutaneously once weekly in combination with Copegus 1000 to 1200 mg PO daily (in 2 divided doses) in 3070 treatment-naïve adults with chronic hepatitis C genotype 1. In this study, lack of early virologic response by treatment Week 12 (subjects who do not achieve undetectable HCV-RNA or ≥ 2 log₁₀ reduction from baseline) was the criteria for discontinuation of treatment. Sustained Virologic Response (SVR) to the treatment was defined as undetectable HCV-RNA (Roche COBAS TaqMan assay, a lower limit of quantitation of 27 IU/mL) at 24 weeks posttreatment (see Table 15).

TABLE 15: Response Rate by Treatment

In all 3 treatment groups, overall SVR rates were similar. In subjects with poor prognostic factors, subjects randomized to PegIntron (peginterferon alfa-2b) (1.5 mcg/kg)/REBETOL or Pegasys/Copegus achieved higher SVR rates compared to those randomized to the PegIntron (peginterferon alfa-2b) (1 mcg/kg)/REBETOL arm. In all arms, SVR rates were lower in subjects with poor prognostic factors compared to those without. For the PegIntron (peginterferon alfa-2b) 1.5 mcg/kg plus REBETOL dose, SVR rates for those with and without, respectively, the following baseline factors were as follows: cirrhosis (10%vs. 42%), normal ALT levels (32%vs. 42%), baseline viral load > 600,000 IU/mL (35% vs. 61%), > 40 years old (38% vs. 50%), and African-American subjects (23%vs. 44%). In subjects with undetectable HCV-RNA at treatment Week 12 who received PegIntron (peginterferon alfa-2b) (1.5 mcg/kg)/REBETOL, the SVR rate was 81%(328/407).

PegIntron (peginterferon alfa-2b) /REBETOL Combination Therapy in Prior Treatment Failures

Study 5: In a noncomparative trial, 2293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were re-treated with PegIntron (peginterferon alfa-2b) , 1.5 mcg/kg subcutaneously, once weekly, in combination with weight-adjusted ribavirin. Eligible patients included prior nonresponders (patients who were HCV-RNA positive at the end of aminimum12weeks of treatment) and prior relapsers (patients who were HCV-RNA negative at the end of aminimum12 weeks of treatment and subsequently relapsed after posttreatment follow-up). Patients who were negative at Week 12were treated for 48weeks and followed for 24 weeks posttreatment. Response to treatment was defined as undetectable HCV-RNA at 24 weeks posttreatment (measured using a research-based test, limit of detection 125 IU/mL). The overall response rate was 22%(497/2293) (99%CI: 19.5, 23.9). Patients with the following characteristics were less likely to benefit from re-treatment: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection.

The re-treatment sustained virologic response rates by baseline characteristics are summarized in Table 16.

TABLE 16: SVR Rates by Baseline Characteristics of Prior Treatment Failures

Achievement of an undetectable HCV-RNA at treatment Week 12 was a strong predictor of sustained virologic response (SVR). In this trial, 1470 (64%) subjects did not achieve an undetectable HCV-RNA at treatment Week 12, and were offered enrollment into long-term treatment trials, due to an inadequate treatment response. Of the 823 (36%) subjects who were HCV-RNA undetectable at treatment Week 12, those infected with genotype 1 had an SVR of 48% (245/507), with a range of responses by fibrosis scores (F4-F2) of 39-55%. Subjects infected with genotype 2/3 who were HCV-RNA undetectable at treatment Week 12 had an overall SVR of 70% (196/281), with a range of responses by fibrosis scores (F4-F2) of 60-83%. For all genotypes, higher fibrosis scores were associated with a decreased likelihood of achieving SVR.

Chronic Hepatitis C in Pediatrics

PegIntron (peginterferon alfa-2b) /REBETOL Combination Therapy

Pediatric Study: Previously untreated pediatric subjects 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV RNA were treated with REBETOL 15mg/kg/day plus PegIntron (peginterferon alfa-2b) 60mcg/m² once weekly for 24 or 48 weeks based on HCV genotype and baseline viral load. All subjects were to be followed for 24 weeks posttreatment. A total of 107 subjects received treatment, of whom 52% were female, 89% were Caucasian, and 67% were infected with HCV genotype 1. Subjects infected with genotype 1, 4 or genotype 3 with HCV RNA ≥ 600,000 IU/mL received 48 weeks of therapy while those infected with genotype 2 or genotype 3 with HCV RNA < 600,000 IU/mL received 24 weeks of therapy. The study results are summarized in Table17.

TABLE 17: Sustained Virologic Response Rates by Genotype and Treatment Duration – Pediatric Study

Last reviewed on RxList: 7/10/2009
This monograph has been modified to include the generic and brand name in many instances.