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Intron A Rebetol

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Intron A - Rebetol

CLINICAL PHARMACOLOGY

Pharmacokinetics

Interferon alfa-2b, recombinant

Single and multiple dose pharmacokinetic properties of INTRON A (interferon alfa-2b, recombinant) are summarized in Table 1 . Following a single 3 million IU (MIU) subcutaneous dose in 12 patients with chronic hepatitis C, mean (% CV*) serum concentrations peaked at 7 (44%) hours. Following 4 weeks of subcutaneous dosing with 3 MIU three times a week (TIW), interferon serum concentrations were undetectable predose. However, a twofold increase in bioavailability was noted upon multiple dosing of interferon; the reason for this is unknown. Mean half-life values following single- and multiple- dose administrations were 6.8 (24%) hours and 6.5 (29%) hours, respectively.

Ribavirin

Single- and multiple- dose pharmacokinetic properties in adults with chronic hepatitis C 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 AUC12 hr , a sixfold 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.

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. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies were conducted without instructions with respect to food consumption. (See DOSAGE AND ADMINISTRATION .)

Effect of Antacid on Absorption of Ribavirin

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

Table 1. Mean (% CV) Pharmacokinetic Parameters for Intron A and Rebetol when administered individually to Adults with Chronic Hepatitis C

Parameter

Intron A (N=12)

Rebetol (N=12)

Single Dose

3 MIU

Multiple Dose

3 MIU tiw

Single Dose

600 mg

Multiple Dose

600 mg bid

Tmax(hr)

7 (44)

5 (37)

1.7 (46) ***

3 (60)

Cmax*

13.9 (32)

29.7 (33)

782 (37)

3680 (85)

AUCtf **

142 (43)

333 (39)

13400 (48)

228000 (25)

T1/2 (hr)

6.8 (24)

6.5 (29)

43.6 (47)

298 (30)

Apparent Volume of Distribution (L)    

2825 (9)

 
Apparent Clearance (L/hr)

14.3 (17)

 

38.2 (40)

 
Absolute Bioavailability    

64% (44)

 


* IU/mL for Intron A and ng/mL for Rebetol

** IU. hr/mL for Intron A and ng. hr/mL for Rebetol

data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N = 5

N = 6

*** n = 11

Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an 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 of 14 C-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.

No pharmacokinetic interactions were noted between INTRON A Injection and REBETOL Capsules in a multiple-dose pharmacokinetic study.

Special Populations

Renal Dysfunction The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to 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). This appears to be due to reduction of apparent clearance in these patients. Ribavirin was not removed by hemodialysis. Rebetol is not recommended for patients with severe renal impairment (see WARNINGS ).

Hepatic Dysfunction The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUC tf values were not 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 C max values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.

Pediatric Patients Pharmacokinetic evaluations for pediatric subjects have not been performed.

Elderly Patients Pharmacokinetic evaluations for elderly subjects have not been performed.

Gender There were no clinically significant pharmacokinetic differences noted in a single-dose study of eighteen male and eighteen female subjects.

* In this section of the label, numbers in parenthesis indicate % coefficient of variation.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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