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

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 x 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.

High‐dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C†

“…6 Unexpect- edly, the formula systematically underestimated the dose of ribavirin. Thus, in general, it was necessary to gradually increase the dose of ribavirin during the first part of the treatment to achieve the chosen target concentration.…”

“…The reasons the formula overestimated the expected concentration of ribavirin for a given dose are being investigated. One possibility is that a small number of samples inappropriately stored in the previous study 6 may have biased the model. It is also possible that the absorption of ribavirin is saturable.…”

“…3 In contrast to current recommendations, we have recently shown that renal function is of greater importance than body weight for ribavirin clearance, and we therefore have suggested the use of a pharmacokinetic formula based primarily on renal function as a tool to determine the accurate dose of ribavirin for treatment. 6 In a previous study, we have shown that with a standard ribavirin treatment dose of 800 to 1200 mg daily, the mean ribavirin concentration was 8.2 mol/L (range, 0-17.7). 7 Other studies have shown a correlation between the ribavirin concentration and viral response.…”

“…6 When necessary, the dose of ribavirin was increased to reach the target concentration, as indicated by the measured plasma ribavirin concentrations. Creatinine clearance was estimated according to the Cockroft-Gault equation.…”

“…Creatinine clearance was estimated according to the Cockroft-Gault equation. 6 Treatment was discontinued in patients who had detectable virus (Ͼ600 IU/mL) after 24 weeks of treatment.…”