From THE INFECTIOUS DISEASE UNIT, DEPARTMENT OF MEDICINE, Karolinska Institutet at Karolinska Unversity Hospital in Huddinge, Stockholm, Sweden RIBAVIRIN – DOSE AND CONCENTRATION IN TREATMENT OF CHRONIC HEPATITIS C INFECTED PATIENTS

Chronic hepatitis C infection is a global health problem with 170 million patients infected. Hepatitis C virus (HCV) infection is a leading cause of end stage liver disease. Current antiviral treatment options available are not optimal either regarding cure of disease or risk of side effects. The aim of the studies in this thesis was to investigate the pharmacokinetic-pharmacodynamic relationships of ribavirin in order to optimise ribavirin treatment for chronic HCV patients. In our first study a population pharmacokinetic analysis was performed using a non-linear mixed modelling evaluating population factors such as age, gender, body weight, serum creatinine and estimated GFR in patients with a wide range of renal function. Ribavirin clearance was found to be dependent on renal function and body weight gave a minor contribution to the final model. Hence, ribavirin dosing should not be based on body weight alone. A formula is presented, which can be used to estimate a ribavirin dose to reach a desired target concentration of ribavirin. The most frequent and serious side effect in ribavirin treatment is anaemia. In our second study we investigated which factors influences ribavirin induced anaemia. Ribavirin plasma concentration and dose per kg body weight versus anaemia was analysed in a non-linear regression model and we found that ribavirin induced anaemia depends on ribavirin plasma concentration, not on dose per body weight. The relation between ribavirin concentration and treatment outcome is not well investigated. In our third study, observed ribavirin concentrations in chronic HCV patients treated with interferon and ribavirin was analysed regarding treatment outcome. In a regression model genotype non-1 infection was found to be a significant predictor of treatment outcome (p<0.001) while type of interferon (standard versus pegylated) and ribavirin plasma concentration were not. In genotype 1 infected patients there was a tendency that sustained viral response was achieved more often in patients with ribavirin concentration above the median concentration of 8.7μM, than below the median. Data are suggesting that higher ribavirin concentrations may lead to better treatment response in genotype 1 infected patients. In our fourth study we investigate safety and feasibility of high ribavirin doses. 10 patients were treated with ribavirin doses aimed to reach a steady state ribavirin plasma concentration above 15 μM. The dose-predicting model from the first study was used, but underestimated the ribavirin dose. After dose adjustments a mean dose was 2540 mg/day. Due to anaemia, 2 patients required blood transfusions, twice. 9 patients completed treatment and 9 patients were cured. In the dose-estimating model from the first study, constant absorption of ribavirin was assumed. Saturable absorption could explain the underestimated dose, and sample instability could have biased the model. In our fifth study relative bioavailability was estimated using the observed ribavirin plasma concentration, divided by the concentration predicted by the model in 24 patients. Higher doses of ribavirin were linearly associated with reduced bioavailability. Stability of ribavirin was investigated in whole blood samples and ribavirin was found to be stable when stored < 24 h in room temperature.