Ribavirin clinical pharmacology

# Clinical Pharmacology

## Pharmacokinetics
Single- and multiple-dose pharmacokinetic properties in adults are summarized in Table 11. 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 to 1200 mg ribavirin. The relationship between dose and Cmax was curvilinear, tending to asymptote above single doses of 400 to 600 mg.
Upon multiple oral dosing, based on AUC12hr, a 6-fold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg twice daily, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 ng/mL (37%). Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.
Effect of Antacid on Absorption of Ribavirin: Coadministration of REBETOL capsules with an antacid containing magnesium, aluminum, and simethicone resulted in a 14% decrease in mean ribavirin AUCtf. The clinical relevance of results from this single-dose study is unknown.
Tissue Distribution: 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.
Metabolism and Excretion: 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.

## 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 greater than 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 nonrenal clearance in these subjects. Phase 3 efficacy trials included subjects with creatinine clearance values greater than 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 less than 50 mL/min should not be treated with REBETOL .
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 trial of 18 male and 18 female subjects.
Pediatric Patients
Multiple-dose pharmacokinetic properties for REBETOL capsules and INTRON A in pediatric subjects with chronic hepatitis C between 5 and 16 years of age are summarized in Table 12. The pharmacokinetics of REBETOL and INTRON A (dose-normalized) are similar in adults and pediatric subjects.
Complete pharmacokinetic characteristics of REBETOL oral solution have not been determined in pediatric subjects. Ribavirin Cmin values were similar following administration of REBETOL oral solution or REBETOL capsules during 48 weeks of therapy in pediatric subjects (3 to 16 years of age).
A clinical trial in pediatric subjects with chronic hepatitis C between 3 and 17 years of age was conducted in which pharmacokinetics for PegIntron and REBETOL (capsules and oral solution) were evaluated. In pediatric subjects receiving body surface area-adjusted dosing of PegIntron at 60 mcg/m2/week, the log transformed ratio estimate of exposure during the dosing interval was predicted to be 58%  higher than observed in adults receiving 1.5 mcg/kg/week. The pharmacokinetics of REBETOL (dose-normalized) in this trial were similar to those reported in a prior study of REBETOL in combination with INTRON A in pediatric subjects and in adults.

## 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 .