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Pegintron and Rebetol

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PegIntron and Rebetol Combo Pack

CLINICAL PHARMACOLOGY

General

The biological activity of Peglntron™ 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 primary effects such as the induction of certain enzymes and suppression of cell proliferation in the interferon receptor bearing cells, and secondary effects including immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. These primary and secondary effects inhibit virus replication in virusinfected cells. Interferon alfa upregulates the Th1 T-helper cell subset in cell culture studies. The clinical relevance of these findings is not known.

The mechanism of inhibition of hepatitis C virus (HCV) RNA by combination therapy with ribavirin and interferon products has not been established.

Pharmacodynamics

Peglntron™ 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

Peginterferon alfa-2b

Following a single subcutaneous (SC) dose of Peglntron™, 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 Peglntron™ increase in a dose-related manner. After multiple dosing, there is an increase in bioavailability of Peglntron™. 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 Peglntron™ elimination half-life is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection. The apparent clearance of Peglntron™ is estimated to be approximately 22.0 mL/hr kg. Renal elimination accounts for 30% of the clearance.

Pegylation of interferon alfa-2b produces a product (Peglntron™) whose clearance is lower than that of non-pegylated interferon alfa-2b. When compared to INTRON® A, Peglntron™ (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, Peglntron™ has approximately ten-fold greater Cmax and 50-fold greater AUC than interferon alfa-2b.

Ribavirin

Single- and multiple-dose pharmacokinetic properties in adults are summarized in TABLE 1. Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUCtf (AUC from time zero to last measurable concentration) following single doses of 200-1200 mg ribavirin. The relationship between dose and Cmax was curvilinear, tending to asymptote above single doses of 400-600 mg.

Upon multiple oral dosing, based on AUC12hn a 6-fold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

TABLE 1: Mean (% Coefficient of Variation) Pharmacokinetic Parameters for REBETOL® When Administered Individually to Adults

Parameter REBETOL®
Single Dose 600 mg Capsules
(N=12)
Multiple Dose 600 mg BID Capsules
(N=12)
T max (hr) 1.7(46)*** 3(60)
Cmax* 782(37) 3680 (85)
AUCtf ** 13400 (48) 228000 (25)
T½ (hr) 43.6 (47) 298 (30)
Apparent Volume of Distribution (L) 2825 (9) †  
Apparent Clearance(L/hr) 38.2 (40)  
Absolute Bioavailability 64% (44)†,†  
*ng/mL
** nghr/mL
*** N = 11
† data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N = 5
†† N = 6

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. There are insufficient data to address the clinical relevance of these results. During clinical studies with Peglntron™/REBETOL®, all subjects were instructed to take REBETOL® Capsules with food. (See DOSAGE AND ADMINISTRATION.)

Effect of Antacid on Absorption of Ribavirin

Coadministration of REBETOL® Capsules with an antacid containing magnesium, aluminum, and simethicone (Mylanta®1) resulted in a 14% decrease in mean ribavirin AUCtf. The clinical relevance of results from this single-dose study is unknown.

Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via es-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins.

Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg 14C-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose.

Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme-mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions.

Special Populations

Renal Dysfunction: Following multiple dosing of Peglntron™ (1 mcg/kg SC given every week for four weeks) the clearance of Peglntron™ is reduced by a mean of 17% in patients with moderate renal impairment (creatinine clearance 30-49 mL/min) and by a mean of 44% in patients with severe renal impairment (creatinine clearance 10-29 mL/min) compared to subjects with normal renal function. Clearance was similar in patients with severe renal impairment not on dialysis and patients who are receiving hemodialysis.

The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to non HCV infected subjects with varying degrees of renal dysfunction. The mean AUCtf value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance > 90 mL/min). In subjects with creatinine clearance values between 30 to 60 mL/min, AUCtf was twofold greater when compared to control subjects. The increased AUCtf appears to be due to reduction of renal and non-renal clearance in these patients. Phase III efficacy trials included subjects with creatinine clearance values > 50 mL/min. The multiple dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine clearance < 50 mL/min should not be treated with Peglntron™/REBETOL® Combo Pack (see PRECAUTIONS).

Hepatic Dysfunction: The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUCtf values were significantly different in subjects with mild, moderate, or severe hepatic dysfunction (Child-Pugh Classification A, B, or C) when compared to control subjects. However, the mean Cmax values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.

Gender: During the 48-week treatment period with Peglntron™, no differences in the pharmacokinetic profiles were observed between male and female patients with chronic hepatitis C infection. In ribavirin trials there were no clinically significant pharmacokinetic differences noted in a single-dose study of eighteen male and eighteen female subjects.

Geriatric Patients: The pharmacokinetics of geriatric subjects ( > 65 years of age) treated with a single subcutaneous dose of 1 mcg/kg of Peglntron™ were similar in Cmax, AUC, clearance, or elimination half-life as compared to younger subjects (28 to 44 years of age). Pharmacokinetic evaluations in elderly subjects with ribavirin have not been performed.

Pediatric Patients: Pharmacokinetic evaluations for combination Peglntron™ and REBETOL® therapy in pediatric subjects have not been performed.

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 patients with chronic hepatitis C who received Peglntron™ (1.5 mcg/kg) once weekly for 4 weeks. Peglntron™ treatment resulted in a 28% (mean) increase in a measure of CYP2C8/9 activity. Peglntron™ treatment also resulted in a 66% (mean) increase in a measure of CYP2D6 activity; however, the effect was variable as 13 patients had an increase, 5 patients had a decrease, and 4 patients had no significant change (See PRECAUTIONS: DRUG INTERACTIONS).

No significant effect was observed on the pharmacokinetics of representative drugs metabolized by CYP1A2, CYP3A4, or N-acetyltransferase. The effects of Peglntron™ on CYP2C19 activity were not assessed.

Methadone: The pharmacokinetics of concomitant administration of methadone and Peglntron™ were evaluated in 18 Peglntron™ naive chronic hepatitis C patients receiving 1.5 mcg/kg/week Peglntron™ SC weekly. All patients were on stable methadone maintenance therapy receiving > 40 mg/day prior to initiating Peglntron™. Mean methadone AUC was approximately 16% higher after 4 weeks of Peglntron™ treatment as compared to baseline. In 2 patients, methadone AUC was approximately double after 4 weeks of Peglntron™ treatment as compared to baseline (See PRECAUTIONS: DRUG INTERACTIONS).

Zidovudine, Lamivudine, and Stavudine: Ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, and stavudine and zidovudine. 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 co-administered as part of a multi-drug regimen to HIV/HCV co-infected patients, (see PRECAUTIONS: DRUG INTERACTIONS).

Didanosine: Exposure to didanosine or its active metabolite (dideoxyadenosine 5'- triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities (See PRECAUTIONS: DRUG INTERACTIONS).

Clinical Studies

Clinical Study 1 evaluated Peglntron monotherapy. See Peglntron Powder for Injection Package Insert for information about this study.

Peglntron™/REBETOL® Combination Therapy-Study 2

A randomized study compared treatment with two Peglntron™/REBETOL® (ribavirin, USP) regimens [Peglntron™ 1.5 mcg/kg SC once weekly (QW)/REBETOL® 800 mg PO daily (in divided doses); Peglntron™ 1.5 mcg/kg SC QW for 4 weeks then 0.5 mcg/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-naive 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 Peglntron™ 1.5 mcg/kg plus ribavirin 800 mg dose was higher than the response rate to INTRON® A/REBETOL® (See Table 2). The response rate to Peglntron™ 1.5→0.5 mcg/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

  Peglntron™ 1.5 mcg/kg QW
REBETOL® 800 mg QD
INTRON® A3 MIU TIW
REBETOL® 1000/1200 mg QD
Overall response 1,2 52% (264/511) 46% (231/505)
Genotype 1 41% (141/348) 33% (112/343)
Genotype 2-6 75% (123/163) 73% (119/162)
1Serum HCV RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory.
2 Difference in overall treatment response (Peglntron™/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. Response to treatment was defined as undetectable HCV RNA (100 copies/mL) at 24 weeks posttreatment.

Patients with viral genotype 1, regardless of viral load, had a lower response rate to Peglntron™ (1.5 mcg/kg)/REBETOL® (800 mg) 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 Peglntron™/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 in this study.

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.

Peglntron™/REBETOL® Combination Therapy-Study 3

In a large United States community-based study (Study 3), 4913 patients with chronic hepatitis C were randomized to receive Peglntron™ 1.5 mcg/kg SC once weekly (QW) in combination with a REBETOL® dose of 800-1400 mg (weight-based dosing- [WBD]) or 800 mg (Flat) PO daily (in divided doses) for 24 or 48 weeks based on genotype. Response to treatment was defined as undetectable (based on an assay with a lower limit of detection of 125 lU/mL) HCV RNA at 24 weeks posttreatment.

Treatment with Peglntron™ 1.5 mcg/kg and REBETOL® 800-1400 mg resulted in a higher sustained virologic response compared to Peglntron™ in combination with a flat 800 mg daily dose of REBETOL® for all treated patients (p=0.01). Subjects weighing > 105 kg obtained the greatest benefit with WBD, although a modest benefit was also observed in subjects weighing > 85-105 kg (Table 3). The benefit of WBD in subjects weighing > 85 kg was observed with HCV genotypes 1-3. Insufficient data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an increased incidence of anemia (see ADVERSE REACTIONS and Laboratory Values).

Table 3:SVR Rate by Treatment and Baseline Weight- Study 3

Treatment Group Subject Baseline Weight
< 65 kg ( < 143 lb) 65-85 kg (143-188 lb) > 85-105 kg ( > 188-231 lb) > 105 kg ( > 231 lb)
WBD* 50% (173/348) 45% (449/994) 42% (351/835) 47% (138/292)
Flat 51% (173/342) 44% (443/1011) 39% (318/819) 33% (91/272)
* p=0.01, primary efficacy comparison ( based on data from subjects weighing 65 kg or higher at baseline and utilizing a logistic regression analysis that includes treatment [WBD or Flat], genotypeand presence/absence of advanced fibrosis, in the model).

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.

Animal Toxicology

Long-term studies in the mouse and rat ( 1 8 - 2 4 months; doses of 20 - 75 and 1 0 - 4 0 mg/kg/day, respectively {estimated human equivalent doses of 1.67 - 6.25 and 1.43 - 5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 - 0.4 X the maximum human 24-hour dose of ribavirin}) have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

Last reviewed on RxList: 6/24/2013
This monograph has been modified to include the generic and brand name in many instances.

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