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PEG-Intron (Peginterferon Alfa-2B) - Description and Clinical Pharmacology

 
 



DESCRIPTION

PEG-Intron® , peginterferon alfa-2b, Powder for Injection is a covalent conjugate of recombinant alfa-2b interferon with monomethoxypolyethylene glycol (PEG). The average molecular weight of the PEG portion of the molecule is 12,000 daltons. The average molecular weight of the PEG-Intron molecule is approximately 31,000 daltons. The specific activity of peginterferon alfa-2b is approximately 0.7 × 108 IU/mg protein.

Interferon alfa-2b, is a water-soluble protein with a molecular weight of 19,271 daltons produced by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid containing an interferon gene from human leukocytes.

PEG-Intron is supplied in both vials and the Redipen™ for subcutaneous use.

Vials

Each vial contains either 74 µg, 118.4 µg, 177.6 µg, or 222 µg of PEG-Intron as a white to off-white tablet-like solid, that is whole/in pieces or as a loose powder, and 1.11 mg dibasic sodium phosphate anhydrous, 1.11 mg monobasic sodium phosphate dihydrate, 59.2 mg sucrose and 0.074 mg polysorbate 80. Following reconstitution with 0.7 mL of the supplied Sterile Water for Injection, USP, each vial contains PEG-Intron at strengths of either 50 µg per 0.5 mL, 80 µg per 0.5 mL, 120 µg per 0.5 mL, or 150 µg per 0.5 mL.

Redipen™

Redipen™ is a dual-chamber glass cartridge containing lyophilized PEG-Intron as a white to off-white tablet or powder that is whole or in pieces in the sterile active chamber and a second chamber containing Sterile Water for Injection, USP. Each PEG-Intron Redipen™ contains either 67.5 µg, 108 µg, 162 µg, or 202.5 µg of PEG-Intron, and 1.013 mg dibasic sodium phosphate anhydrous, 1.013 mg monobasic sodium phosphate dihydrate, 54 mg sucrose and 0.0675 mg polysorbate 80. Each cartridge is reconstituted to allow for the administration of up to 0.5 mL of solution. Following reconstitution, each Redipen™ contains PEG-Intron at strengths of either 50 µg per 0.5 mL, 80 µg per 0.5 mL, 120 µg per 0.5 mL, or 150 µg per 0.5 mL for a single use. Because a small volume of reconstituted solution is lost during preparation of PEG-Intron, each Redipen™ contains an excess amount of PEG-Intron powder and diluent to ensure delivery of the labeled dose.

CLINICAL PHARMACOLOGY

General:    The biological activity of PEG-Intron is derived from its interferon alfa-2b moiety. Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface and initiate a complex sequence of intracellular events. These include the induction of certain enzymes, suppression of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells. Interferon alfa upregulates the Th1 T-helper cell subset in in vitro studies. The clinical relevance of these findings is not known.

Pharmacodynamics:    PEG-Intron 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 (SC) dose of PEG-Intron, the mean absorption half-life (t ½ ka) was 4.6 hours. Maximal serum concentrations (Cmax) occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours. The Cmax and AUC measurements of PEG-Intron increase in a dose-related manner. After multiple dosing, there is an increase in bioavailability of PEG-Intron. Week 48 mean 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 PEG-Intron elimination half-life is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection. The apparent clearance of PEG-Intron is estimated to be approximately 22.0 mL/hr·kg. Renal elimination accounts for 30% of the clearance. Single dose peginterferon alfa-2b pharmacokinetics following a subcutaneous 1.0 µg/kg dose suggest the clearance of peginterferon alfa-2b is reduced by approximately half in subjects with impaired renal function (creatinine clearance <50 mL/minute).

Pegylation of interferon alfa-2b produces a product (PEG-Intron) whose clearance is lower than that of non-pegylated interferon alfa-2b. When compared to INTRON A, PEG-Intron (1.0 µg/kg) has approximately a seven-fold lower mean apparent clearance and a five-fold greater mean half-life permitting a reduced dosing frequency. At effective therapeutic doses, PEG-Intron has approximately ten-fold greater Cmax and 50-fold greater AUC than interferon alfa-2b.

The pharmacokinetics of geriatric subjects (>65 years of age) treated with a single subcutaneous dose of 1.0 µg/kg of PEG-Intron were similar in Cmax, AUC, clearance, or elimination half-life as compared to younger subjects (28 to 44 years of age).

During the 48 week treatment period with PEG-Intron, no differences in the pharmacokinetic profiles were observed between male and female patients with chronic hepatitis C infection.

Effect of Food on Absorption of Ribavirin Both AUCtf 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:    It is not known if PEG-Intron therapy causes clinically significant drug-drug interactions with drugs metabolized by the liver in patients with hepatitis C. In 12 healthy subjects known to be CYP2D6 extensive metabolizers, a single subcutaneous dose of 1 µg/kg PEG-Intron did not inhibit CYP1A2, 2C8/9, 2D6, hepatic 3A4 or N-acetyltransferase; the effects of PEG-Intron on CYP2C19 were not assessed.

CLINICAL STUDIES

PEG-INTRON MONOTHERAPY-STUDY 1

A randomized study compared treatment with PEG-Intron (0.5, 1.0, or 1.5 µg/kg once weekly SC) to treatment with INTRON A, (3 million units three times weekly SC) in 1219 adults with chronic hepatitis from HCV infection. The patients were not previously treated with interferon alfa, had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis. Patients were treated for 48 weeks and were followed for 24 weeks post-treatment. Seventy percent of all patients were infected with HCV genotype 1, and 74 percent of all patients had high baseline levels of HCV RNA (more than 2 million copies per mL of serum), two 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 1.0 and 1.5 µg/kg PEG-Intron doses were similar (approximately 24%) to each other and were both higher than the response rate to INTRON A (12%). (See Table 1)

TABLE 1. Rates of Response to Treatment-Study 1
A
PEG-Intron
0.5 µg/kg
(N=315)
B
PEG-Intron
1.0 µg/kg
(N=298)
C
INTRON A
3 MIU TIW
(N=307)
B-C
(95% CI)
Difference between
PEG-Intron 1.0 µg/kg
and INTRON A
Treatment Response (Combined Virologic Response and ALT Normalization) 17% 24% 12% 11 (5, 18)
Virologic Response a 18% 25% 12% 12 (6, 19)
ALT Normalization 24% 29% 18% 11 (5, 18)
a Serum HCV is measured by a research-based quantitative polymerase chain reaction assay by a central laboratory.

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

Patients receiving PEG-Intron with viral genotype 1 had a response rate of 14% (28/199) while patients with other viral genotypes had a 45% (43/96) response rate.

Ninety-six percent of the responders in the PEG-Intron 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 patients 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 patients. A modest reduction in inflammation compared to baseline that was similar in all four treatment groups was observed.

PEG-INTRON/REBETOL COMBINATION THERAPY-STUDY 2

A randomized study compared treatment with two PEG-Intron/REBETOL regimens [PEG-Intron 1.5 µg/kg SC once weekly (QW)/REBETOL 800 mg PO daily (in divided doses); PEG-Intron 1.5 µg/kg SC QW for 4 weeks then 0.5 µg/kg SC QW for 44 weeks/REBETOL 1000/1200 mg PO daily (in divided doses)] with INTRON A [3 MIU SC thrice weekly (TIW)/REBETOL 1000/1200 mg PO daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon na[iuml ]ve patients were treated for 48 weeks and followed for 24 weeks posttreatment. Eligible patients 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 PEG-Intron 1.5 µg/kg plus ribavirin 800 mg dose was higher than the response rate to INTRON A/REBETOL (See Table 2). The response rate to PEG-Intron 1.5 -> 0.5 µg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

TABLE 2. Rates of Response to Treatment-Study 2
PEG-Intron 1.5 µg/kg QW
REBETOL 800 mg QD
INTRON A 3 MIU TIW
REBETOL 1000/1200 mg QD
Overall 1 , 2 response 52% (264/511) 46% (231/505)
Genotype 1 41% (141/348) 33% (112/343)
Genotype 2-6 75% (123/163) 73% (119/162)
1 Serum HCV RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory.
2 Difference in overall treatment response (PEG-Intron/REBETOL vs. INTRON A/REBETOL) is 6% with 95% confidence interval of (0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at baseline.

Patients with viral genotype 1, regardless of viral load, had a lower response rate to PEG-Intron (1.5 µg/kg)/REBETOL compared to patients with other viral genotypes. Patients 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.

Patients with lower body weight tended to have higher adverse event rates (see ADVERSE REACTIONS) and higher response rates than patients with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PEG-Intron/REBETOL were 49% in men and 56% in women. Response rates were lower in African American and Hispanic patients 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.

Liver biopsies were obtained before and after treatment in 68% of patients. Compared to baseline approximately 2/3 of patients in all treatment groups were observed to have a modest reduction in inflammation.

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