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 3450 ribavirin serum concentrations from 1105 patients at different treatment weeks for inclusion in the analysis. Population factors included gender, age, body weight, serum creatinine, creatinine clearance, and previous interferon 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 weight, gender, age, and serum creatinine affected CL/F. Population mean CL/F estimates were 17.9 L/h (female) and 21.5 L/h (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 approximately 28%. The four covariates in the model explained 27% of this variability, and were thus of limited clinical significance because of the substantial residual variability not accounted for by the model. In assessing the relationship between pharmacokinetics and pharmacodynamics, the week 4 hemoglobin nadir value was negatively associated with week 4 ribavirin concentrations. The percentage of reduction from baseline was positively associated with ribavirin concentrations, although these data were highly variable. Loss of HCV-RNA at 24 weeks after completion of treatment was considered a response to interferon and ribavirin treatment in a logistic regression analysis of clinical and pharmacokinetic variables and treatment response in the interferon-naive patients. Hepatitis C virus genotype, pretreatment HCV-RNA titer, duration of treatment period, week 4 ribavirin concentration, and patient age affected the likelihood of response. Higher ribavirin concentrations at treatment week 4 were associated with a higher response rate. Variables that have predictive value for treatment outcome in patients treated with interferon and ribavirin are similar to those previously reported for interferon monotherapy.

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.

This analysis confirms earlier observations of progressive pharmacokinetic changes in the patients with hepatitis C during 48 weeks of treatment. The absence of a relationship between toxicity or efficacy variables and interferon concentration or activity (within a dose level) suggests that clinical management of patients (eg, for efficacy or to manage toxicity) should be based on clinically derived dosing guidelines rather than on serum concentration or activity criteria.

The current dose regimen is administered according to BSA which is the most important factor influencing temozolomide clearance. No further dose adjustment is required.

Aims To assess the dose selection using population pharmacokinetics of Pegylated Intron‐α2b (PEG‐Intron) in patients with chronic myelogenous leukaemia (CML). Methods PEG‐Intron 3–6 µg kg−1 was administered subcutaneously once a week and blood samples were collected up to 48 weeks of treatment. A total of 624 samples collected from 137 patients were included in the analysis. Nonlinear mixed‐effects modelling was used to analyse the sparsely sampled concentration data from a clinical efficacy trial. Covariates in the analysis included weight, sex, age, race, serum creatinine and estimated creatinine clearance (CLcr). Results The apparent clearance of PEG‐Intron decreased after repeated dosing. The clearance at treatment week 4 was 42.3 l day−1 (patients with CLcr 120 ml min−1) with interpatient variability 30%. At treatment week 48, the clearance value was reduced to 69% of its week 4 value. CLcr, a composite variable calculated from body weight, sex, age and serum creatinine, had a small but statistically significant influence on the clearance of PEG‐Intron. The clearance of PEG‐Intron in patients with CML was 40% higher than that of hepatitis C virus‐infected patients. Conclusion The dose of PEG‐Intron 6.0 µg kg−1 week−1 appeared appropriate in the treatment of patients with CML.