Dosage of Ribavirin in Patients With Hepatitis C Should Be Based on Renal Function: A Population Pharmacokinetic Analysis

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Abstract
A combination of interferon alfa and ribavirin is standard therapy for chronic hepatitis C virus (HCV). Ribavirin dosage is currently based on body weight. The aim of this study was to critically evaluate current dosage recommendations on the basis of a population pharmacokinetic analysis. The data consisted of 383 ribavirin plasma concentration samples collected from 63 patients undergoing treatment of HCV. Forty-four patients had normal range serum creatinine with an estimated glomerular filtration rate (GFR = estimated creatinine clearance) of 57–144 mL/min. Another 19 patients had renal impairment with a GFR of 5–57 mL/min. Population factors were age, gender, body weight, serum creatinine, and GFR. A population pharmacokinetic analysis with a two-compartment model was carried out using nonlinear mixed effect modeling. Ribavirin clearance was found to be linearly dependent on renal function with a small nonrenal clearance dependent on body weight and age. Estimated GFR was a significantly better predictor of ribavirin clearance than body weight alone. There remained a significant 40% interindividual variability in ribavirin total clearance not explained by estimated GFR and body weight. The volume of distribution was large and proportional to body weight (V = 44.3 × body weight), which resulted in a long half-life (100–500 hours, depending on GFR) and a long time to steady state (3–12 weeks). Ribavirin dosage should mainly be based on renal function and not, as currently recommended, on body weight alone. A ribavirin-dosing schedule based on GFR and body weight to reach an intended target concentration is proposed. Ribavirin monitoring may be useful for optimizing HCV treatment not only in patients with renal insufficiency but also in other patients considering the time to steady state and the interindividual variability in ribavirin clearance.