Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body weight >75 kg) AUC0-12hr was 25,361±7110 ng·hr/mL and Cmax was 2748±818 ng/mL. The average time to reach Cmax was 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662±545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112±810 ng/mL in patients who received 1200 mg/day (n=75; body weight >75 kg).
The terminal half-life of ribavirin following administration of a single oral dose of ribavirin is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the Cmax at steady state was four-fold higher than that of a single dose.
Effect of Food on Absorption of Ribavirin
Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%, respectively, when ribavirin was taken with a high-fat meal compared with fasting conditions (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Elimination and Metabolism
The contribution of renal and hepatic pathways to ribavirin elimination after administration of ribavirin is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.
A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.
The pharmacokinetics of ribavirin following administration of ribavirin have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin in patients with creatinine clearance <50 mL/min. Therefore, patients with creatinine clearance <50 mL/min should not be treated with ribavirin (see WARNINGS and DOSAGE AND ADMINISTRATION).
The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin has not been evaluated. The clinical trials of ribavirin were restricted to patients with Child-Pugh class A disease.
Pharmacokinetic evaluations in pediatric patients have not been performed.
Pharmacokinetic evaluations in elderly patients have not been performed.
Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.
In vitro studies indicate that ribavirin does not inhibit CYP450 enzymes.
In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine.
In vitro, 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).
Drugs Metabolized by Cytochrome P450
There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.
Treatment with peginterferon alfa-2a once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC (see PRECAUTIONS: Drug Interactions).