CLINICAL PHARMACOLOGY
Pharmacokinetics
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 AUC12hr, 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 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. Clinical efficacy studies with REBETOL/INTRON® A were conducted without instructions with respect to food consumption. During clinical studies with REBETOL/PegIntron™, 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®Trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.) 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 REBETOL When Administered Individually to Adults | Parameter | REBETOL | |
|---|
| | Single Dose
600 mg Oral Solution
(N=14) | Single Dose
600 mg Capsules
(N=12) | Multiple Dose
600 mg BID Capsules
(N=12) |
|---|
| T max (hr) | 1.00(34) | 1.7 (46)N = 11 | 3 (60) |
| Cmaxng/mL | 872 (42) | 782 (37) | 3680 (85) |
| AUCtfng.hr/mL | 14098 (38) | 13400 (48) | 228000 (25) |
| T1/2 (hr) | | 43.6 (47) | 298 (30) |
| Apparent Volume of Distribution (L) | | 2825 (9)data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N = 5 | |
| Apparent Clearance (L/hr) | | 38.2 (40) | |
| Absolute Bioavailability | | 64% (44)N = 6 | |
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 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.
No pharmacokinetic interactions were noted between INTRON A for Injection and REBETOL Capsules in a multiple-dose pharmacokinetic study.
Drug Interactions
Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine and stavudine which could lead to decreased antiretroviral activity. 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 section).
Special Populations
Renal Dysfunction
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 REBETOL (see WARNINGS).
Hepatic Dysfunction
The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUCtf 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 Cmax values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.
Elderly Patients
Pharmacokinetic evaluations in 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.
Pediatric Patients
Multiple-dose pharmacokinetic properties for REBETOL Capsules and INTRON A in pediatric patients with chronic hepatitis C between 5 and 16 years of age are summarized in TABLE 2. The pharmacokinetics of REBETOL and INTRON A (dose-normalized) are similar in adults and pediatric patients.
Complete pharmacokinetic characteristics of REBETOL Oral Solution have not been determined in pediatric patients. Ribavirin Cmin values were similar following administration of REBETOL Oral Solution or REBETOL Capsules during 48 weeks of therapy in pediatric patients (3 to 16 years of age).
TABLE 2. Mean (% CV) Multiple-Dose Pharmacokinetic Parameters for INTRON A and REBETOL Capsules When Administered to Pediatric Patients With Chronic Hepatitis C | Parameter | REBETOL
15mg/ kg/ day as 2 divided doses
(N=17) | INTRON A
3MIU/m2
TIW
(N=54) |
|---|
| Tmax (hr) | 1.9 (83) | 5.9 (36) |
| Cmax (ng/mL) | 3275 (25) | 51(48) |
AUCAUC12 (ng.hr/mL) for REBETOL; AUC0–24 (IU.hr/mL) for INTRON A
ND=not done | 29774 (26) | 622 (48) |
| Apparent clearance L/hr/kg | 0.27 (27) | ND |
* In this section of the label, numbers in parenthesis indicate % coefficient of variation.
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