Individualized pharmacokinetically guided dosage adjustment of fluorouracil using population pharmacokinetic modeling

vii ABSTRACT David Čechlovský‡ , Stefanie Kraff*, Ulrich Jaehde* *Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Germany ‡ Department of social and clinical pharmacy, Faculty of pharmacy in Hradec Králové, Charles University in Prague Title of diploma thesis: Individualized pharmacokinetically guided dosage adjustment of fluorouracil (5-FU) using population pharmacokinetic modelling. Objectives: To develop a method to increase the efficacy and tolerability of fluorouracil (5-FU) with pharmacokinetically-guided dose adjustment based on a target AUC. Methods: Blood samples were collected from 90 patients with the diagnosis of colorectal carcinoma treated with fluorouracil (5-FU) administered at various infusion durations. Several versions of compartmental pharmacokinetic models were fitted to the plasma concentration data, using nonlinear mixed effect modelling (NONMEM). Different error models were evaluated. The potential effect of patient covariates was evaluated using a stepwise method. Model evaluation was performed by using the bootstrap method. Results: The one-compartment linear model was chosen as a base model as it was successful in fitting to the data collected..The final model contained Additive Residual Error. A covariate BSA>CL and IIV on CL were significantly correlated to the..