title: Ribavirin dosing in chronic hepatitis C: application of population pharmacokinetic-pharmacodynamic models.
abstract: BACKGROUND
  Combination therapy of ribavirin with interferon alfa-2b and pegylated interferon alfa-2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight.
  
  
  OBJECTIVE
  Our objective was to evaluate ribavirin dosing strategies by comparison of their relative efficacy and toxicity profiles.
  
  
  METHODS
  Three models were developed on the basis of data collected from a large phase III trial. A population pharmacokinetic model was used to describe the ribavirin dose-concentration relationship and the influence of covariates. Logistic regression models were developed for both sustained virologic response and hematologic toxicity. Ribavirin concentration was an important explanatory variable for both response and toxicity. Simulations of these models were developed for different ribavirin doses to obtain efficacy and toxicity profiles across the various dosing strategies. These strategies included a fixed 800-mg/d dose, empiric weight-adjusted doses (ie, 1000 mg/d for patients who weighed < or =75 kg and 1200 mg/d for patients who weighed >75 kg [1000/1200 mg/d on the basis of body weights < or =75/>75 kg] and 800 mg/d for patients who weighed <65 kg, 1000 mg/d for patients who weighed from 65 to 85 kg, and 1200 mg/d for patients who weighed >85 kg [800/1000/1200 mg/d on the basis of body weights <65/65-85/>85 kg]), a dose of 13 mg/kg per day, and other per-body weight doses between 9 and 16 mg/kg per day.
  
  
  RESULTS
  Simulation results showed that both efficacy and toxicity increased as the milligrams-per-kilogram dose of ribavirin increased. The body weight-based 800/1000/1200-mg/d dose had overall response and toxicity rates that were 6.3% and 2.5% higher than those of the fixed 800-mg/d dose. In particular, patients with genotype-1 disease had a 7.4% increase in response rate. There were no differences in response and toxicity rates between the 800/1000/1200-mg/d and 13-mg/kg per day dose groups.
  
  
  CONCLUSIONS
  This simulation suggests that ribavirin dosage (in combination with pegylated interferon alfa-2b) for patients with chronic hepatitis C should be based on body weight.
authors.affiliation: Department of Statistics, Schering-Plough Research Institute, Kenilworth, NJ, USA. frank.jen@pharma.novartis.com
authors.forename: Juif
authors.initials: J
authors.lastname: Jen
authors.forename: Mark
authors.initials: M
authors.lastname: Laughlin
authors.forename: Carol
authors.initials: C
authors.lastname: Chung
authors.forename: Samuel
authors.initials: S
authors.lastname: Heft
authors.forename: Melton B
authors.initials: MB
authors.lastname: Affrime
authors.forename: Samir K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Paul
authors.initials: P
authors.lastname: Glue
authors.forename: Gerald
authors.initials: G
authors.lastname: Hajian
mesh_terms: D000328:Adult; D000368:Aged; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D016015:Logistic Models; D008297:Male; D008954:Models, Biological; D012254:Ribavirin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D012254:Ribavirin