Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C

The population pharmacokinetics of ribavirin were assessed in patients with chronic hepatitis C virus (HCV) infection treated with interferon alpha-2b and ribavirin in four clinical efficacy studies. The authors collected 345 0 ribavirin serum concentrations from 1105 patients at different treatment weeks for inclusion in the analysis. Population Factors included gender, ag e, body weight, serum creatinine, creatinine clearance, and previous interf eron treatment history. Ribavirin apparent clearance (CL/F) was calculated from individual patients' daily doses divided by concentration values, and the influence of these factors was assessed by multiple regression. Body we ight, Sender, age, and serum creatinine affected CL/F. Population mean CL/F estimates were 17.9 Lk (female) and 21.5 Lih (male) assuming an age of 40 years and body weight of 70 kg. Ribavirin apparent clearance increased as a function of body weight and decreased at ages greater than 40 years. Serum creatinine had little influence on CL/F, which may reflect the relatively normal renal function of these patients. Total CL/F variability was approxi mately 28%. The four covariates in the model explained 27% of this variabil ity, and were thus of limited clinical significance because of the substant ial residual variability not accounted for by the model. In assessing the r elationship between pharmacokinetics and pharmacodynamics, the week 4 hemog lobin nadir value was negatively associated with week 4 ribavirin concentra tions. The percentage of reduction from baseline was positively associated with ribavirin concentrations, although these data were highly variable. Lo ss of HCV-RNA at 24 weeks after completion of treatment was considered a re sponse to interferon and ribavirin treatment in a logistic regression analy sis of clinical and pharmacokinetic variables and treatment response in the interferon-naive patients. Hepatitis C virus genotype, pretreatment HCV-RN A titer, duration of treatment period, week 4 ribavirin concentration, and patient age affected the likelihood of response. Higher ribavirin concentra tions at treatment week 4 were associated with a higher response rate. Vari ables that have predictive value for treatment outcome in patients treated with interferon and ribavirin are similar to those previously reported for interferon monotherapy.