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Pegasys (Peginterferon Alfa-2a) - Description and Clinical Pharmacology

 
 



DESCRIPTION

PEGASYS, peginterferon alfa-2a, is a covalent conjugate of recombinant alfa-2a interferon (approximate molecular weight [MW] 20,000 daltons) with a single branched bis-monomethoxy polyethylene glycol (PEG) chain (approximate MW 40,000 daltons). The PEG moiety is linked at a single site to the interferon alfa moiety via a stable amide bond to lysine. Peginterferon alfa-2a has an approximate molecular weight of 60,000 daltons. Interferon alfa-2a is produced using recombinant DNA technology in which a cloned human leukocyte interferon gene is inserted into and expressed in Escherichia coli.

PEGASYS is supplied as an injectable solution in vials and prefilled syringes.

180 µg/1.0 mL Vial: A vial contains approximately 1.2 mL of solution to deliver 1.0 mL of drug product. Subcutaneous (sc) administration of 1.0 mL delivers 180 µg of drug product (expressed as the amount of interferon alfa-2a), 8.0 mg sodium chloride, 0.05 mg polysorbate 80, 10.0 mg benzyl alcohol, 2.62 mg sodium acetate trihydrate, and 0.05 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0 ± 0.5.

180 µg/0.5 mL Prefilled Syringe: Each syringe contains 0.6 mL of solution to deliver 0.5 mL of drug product. Subcutaneous (sc) administration of 0.5 mL delivers 180 µg of drug product (expressed as the amount of interferon alfa-2a), 4.0 mg sodium chloride, 0.025 mg polysorbate 80, 5.0 mg benzyl alcohol, 1.3085 mg sodium acetate trihydrate, and 0.0231 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0 ± 0.5.

CLINICAL PHARMACOLOGY

PHARMACODYNAMICS

Interferons bind to specific receptors on the cell surface initiating intracellular signaling via a complex cascade of protein-protein interactions leading to rapid activation of gene transcription. Interferon-stimulated genes modulate many biological effects including the inhibition of viral replication in infected cells, inhibition of cell proliferation and immunomodulation. The clinical relevance of these in vitro activities is not known.

PEGASYS stimulates the production of effector proteins such as serum neopterin and 2', 5'-oligoadenylate synthetase.

PHARMACOKINETICS

Maximal serum concentrations (Cmax) occur between 72 to 96 hours post-dose. The Cmax and AUC measurements of PEGASYS increase in a dose-related manner. Week 48 mean trough concentrations (16 ng/mL; range 4 to 28) at 168 hours post-dose are approximately 2-fold higher than week 1 mean trough concentrations (8 ng/mL; range 0 to 15). Steady-state serum levels are reached within 5 to 8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2.0.

The mean systemic clearance in healthy subjects given PEGASYS was 94 mL/h, which is approximately 100-fold lower than that for interferon alfa-2a (ROFERON® -A). The mean terminal half-life after sc dosing in patients with chronic hepatitis C was 80 hours (range 50 to 140 hours) compared to 5.1 hours (range 3.7 to 8.5 hours) for ROFERON® -A.

SPECIAL POPULATIONS

GENDER AND AGE

PEGASYS administration yielded similar pharmacokinetics in male and female healthy subjects. The AUC was increased from 1295 to 1663 ng·h/mL in subjects older than 62 years taking 180 µg PEGASYS, but peak concentrations were similar (9 vs 10 ng/mL) in those older and younger than 62 years.

PEDIATRIC PATIENTS

The pharmacokinetics of PEGASYS have not been adequately studied in pediatric patients.

RENAL DYSFUNCTION

In patients with end stage renal disease undergoing hemodialysis, there is a 25% to 45% reduction in PEGASYS clearance (see PRECAUTIONS: Renal Impairment).

The pharmacokinetics of ribavirin following administration of COPEGUS have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of COPEGUS in patients with creatinine clearance <50 mL/min. Therefore, patients with creatinine clearance <50 mL/min should not be treated with COPEGUS (see WARNINGS and DOSAGE AND ADMINISTRATION).

EFFECT OF FOOD ON ABSORPTION OF RIBAVIRIN

Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%, respectively, when COPEGUS was taken with a high-fat meal compared with fasting conditions (see DOSAGE AND ADMINISTRATION).

DRUG INTERACTIONS

NUCLEOSIDE ANALOGUES

Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine and stavudine, which could lead to decreased anti-retroviral activity. Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is co-administered with ribavirin (see PRECAUTIONS: Drug Interactions).

METHADONE

The pharmacokinetics of concomitant administration of methadone and PEGASYS were evaluated in 24 PEGASYS na[iuml ]ve chronic hepatitis C patients (15 male, 9 female) who received 180 mg PEGASYS subcutaneously weekly. All patients were on stable methadone maintenance therapy (median dose 95 mg, range 30 mg to 150 mg) prior to receiving PEGASYS. Mean methadone PK parameters were 10% to 15% higher after 4 weeks of PEGASYS treatment as compared to baseline (see PRECAUTIONS: Drug Interactions). Methadone did not significantly alter the PK of PEGASYS as compared to a PK study of 6 chronic hepatitis C patients not receiving methadone.

CLINICAL STUDIES

PEGASYS MONOTHERAPY (STUDIES 1, 2, AND 3)

The safety and effectiveness of PEGASYS for the treatment of hepatitis C virus infection were assessed in three randomized, open-label, active-controlled clinical studies. All patients were adults, had compensated liver disease, detectable hepatitis C virus (HCV), liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. All patients received therapy by sc injection for 48 weeks, and were followed for an additional 24 weeks to assess the durability of response. In studies 1 and 2, approximately 20% of subjects had cirrhosis or bridging fibrosis. Study 3 enrolled patients with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%).

In study 1 (n=630), patients received either ROFERON-A (interferon alfa-2a) 3 MIU three times/week (tiw), PEGASYS 135 µg once each week (qw) or PEGASYS 180 µg qw. In study 2 (n=526), patients received either ROFERON-A 6 MIU tiw for 12 weeks followed by 3 MIU tiw for 36 weeks or PEGASYS 180 µg qw. In study 3 (n=269), patients received ROFERON-A 3 MIU tiw, PEGASYS 90 µg qw or PEGASYS 180 µg once each week.

In all three studies, treatment with PEGASYS 180 µg resulted in significantly more patients who experienced a sustained response (defined as undetectable HCV RNA and normalization of ALT on or after study week 68) compared to treatment with ROFERON-A. In study 1, response to PEGASYS 135 µg was not different from response to 180 µg. In study 3, response to PEGASYS 90 µg was intermediate between PEGASYS 180 µg and ROFERON-A.

Table 1   Sustained Response to Monotherapy Treatment
Study 1
ROFERON-A
3 MIU (N=207)
PEGASYS
180 µg (N=208)
DIFF * (95% Cl)
Combined Virologic and Biologic
Sustained Response
11% 24% 13
(6, 20)
Sustained Virologic Response ** 11% 26% 15
(8, 23)
 *Percent difference between PEGASYS and Roferon-A treatment
**COBAS AMPLICOR® HCV Test, version 2.0
Table 1  (Con't))     Sustained Response to   Monotherapy Treatment
Study 2
ROFERON-A
6/3 MIU (N=261)
PEGASYS
180 µg (N=265)
DIFF * (95% Cl)
Combined Virologic and Biologic
Sustained Response
17% 35% 18
(11, 25)
Sustained Virologic Response ** 19% 38% 19
(11, 26)
 *Percent difference between PEGASYS and Roferon-A treatment
**COBAS AMPLICOR® HCV Test, version 2.0
Table 1 (con't)       Sustained Response to           Monotherapy Treatment
Study 3
ROFERON-A
3 MIU (N=86)
PEGASYS
180 µg (N=87)
DIFF * (95% Cl)
Combined Virologic and Biologic
Sustained Response
7% 23% 16
(6, 26)
Sustained Virologic Response ** 8% 30% 22
(11, 33)
 *Percent difference between PEGASYS and Roferon-A treatment
**COBAS AMPLICOR® HCV Test, version 2.0

 

Matched pre- and post-treatment liver biopsies were obtained in approximately 70% of patients. Similar modest reductions in inflammation compared to baseline were observed in all treatment groups.

Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2log10 drop in HCV RNA titer from baseline by 12 weeks of PEGASYS 180 µg therapy, 2% (3/156) achieved a sustained virologic response (see DOSAGE AND ADMINISTRATION).

Averaged over study 1, study 2, and study 3, response rates to PEGASYS were 23% among patients with viral genotype 1 and 48% in patients with other viral genotypes. The treatment response rates were similar in men and women.

PEGASYS/COPEGUS COMBINATION THERAPY (STUDIES 4 AND 5)

The safety and effectiveness of PEGASYS in combination with COPEGUS for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A).

In study 4, patients were randomized to receive either PEGASYS 180 µg sc once weekly (qw) with an oral placebo, PEGASYS 180 µg qw with COPEGUS 1000 mg po (body weight <75 kg) or 1200 mg po (body weight >/=75 kg) or REBETRON™ (interferon alfa-2b 3 MIU sc tiw plus ribavirin 1000 mg or 1200 mg po). All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded. PEGASYS in combination with COPEGUS resulted in a higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to PEGASYS alone or interferon alfa-2b and ribavirin. In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate.

Table 2    Sustained Virologic Response to Combination Therapy (Study 4)
Interferon alfa-2b+ Ribavirin 1000 mg or 1200 mg PEGASYS + Placebo PEGASYS + COPEGUS 1000 mg or 1200 mg
All patients 197/444 (44%) 65/224 (29%) 241/453 (53%)
Genotype 1 103/285 (36%) 29/145 (20%) 132/298 (44%)
Genotypes 2-6 94/159 (59%) 36/79 (46%) 109/155 (70%)
Difference in overall treatment response (PEGASYS/COPEGUS - Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3).

In study 5, all patients received PEGASYS 180 µg sc qw and were randomized to treatment for either 24 or 48 weeks and to a COPEGUS dose of either 800 mg or 1000 mg/1200 mg (for body weight <75 kg / >/=75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as >2 × 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.

GENOTYPE 1

Irrespective of baseline viral titer, treatment for 48 weeks with PEGASYS and 1000 mg or 1200 mg of COPEGUS resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg COPEGUS.

GENOTYPE NON-1

Irrespective of baseline viral titer, treatment for 24 weeks with PEGASYS and 800 mg of COPEGUS resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of COPEGUS.

Table 3    Sustained Virologic Response as a Function of Genotype (Study 5)
  24 Weeks Treatment 48 Weeks Treatment
  PEGASYS +
COPEGUS
800 mg (N=207)
PEGASYS +
COPEGUS
1000 mg or 1200 mg * (N=280)
PEGASYS +
COPEGUS
800 mg (N=361)
PEGASYS +
COPEGUS
1000 mg or 1200 mg * (N=436)
Genotype 1 29/101 (29%) 48/118 (41%) 99/250 (40%) 138/271 (51%)
Genotype 2-3 79/96 (82%) 116/144 (81%) 75/99 (76%) 117/153 (76%)
*1000 mg for body weight <75 kg; 1200 mg for body weight >/=75 kg.

Among the 36 patients with genotype 4, response rates were similar to those observed in patients with genotype 1 (data not shown). The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.

TREATMENT RESPONSE IN PATIENT SUBGROUPS

Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies 4 and 5, treatment response rates were lower in patients older than 40 years (50% vs 66%), in patients with cirrhosis (47% vs 59%), in patients weighing over 85 kg (49% vs 60%), and in patients with genotype 1 with high vs low viral load (43% vs 56%). African American patients had lower response rates compared to Caucasians.

Paired liver biopsies were performed on approximately 20% of patients in studies 4 and 5. Modest reductions in inflammation compared to baseline were seen in all treatment groups.

In studies 4 and 5, lack of early virologic response at 12 weeks (defined as HCV RNA undetectable or >2log10 lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response at 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response at 24 weeks, nineteen completed a full course of therapy and none achieved an SVR.

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