The objective of this study was to develop a population pharmacokinetic model and validate it using a Bayesian approach for predicting, a priori and a posteriori, the individual volume of distribution (V(d)) and clearance (Cl) of 5-fluorouracil (5-FU) given as short-term intravenous infusion in weekly and multiple doses. Forty-four patients were divided in group A (5-FU weekly doses) including 27 patients with nonmetastatic colorectal adenocarcinoma treated with 450 mg/m(2) of 5-FU, 1 day per week for 48 doses, plus oral levamisol (50 mg/8 h) for 3 days, every 15 days and group B (5-FU multiple doses) including 17 patients with metastatic colorectal adenocarcinoma, receiving 5-FU (425 mg/m(2)) plus intravenous folinic acid (20 mg/m(2)) over 5 consecutive days, every 4 weeks for six cycles. In both groups 5-FU was administered as a 30-60-min infusion. A total of 176 plasma concentrations were analyzed using a NONMEM program according to a linear one-compartment model. In group A, 5-FU population pharmacokinetic parameters were obtained and the covariables studied were age, gender, weight, ideal body weight, height, body surface area, creatinine clearance, and hepatic function tests. A priori and a posteriori validation of this model was carried out with plasma concentrations obtained in day 1 in group B. In group B, population pharmacokinetic parameters of 5-FU following multiple doses were estimated using scale factors to identify differences in 5-FU V(d) and Cl between days 1 and 4, and the interindividual, interoccasion, and residual variabilities studied. V(d) was 0.266 L/kg of ideal body weight and Cl was 1.21 L/h. kg of total weight following weekly doses. The plasma sample obtained at 10 min gave the best accuracy and precision predictions. When 5-FU was administered in multiple doses, the Cl of the drug in day 4 is reduced by 30.14% compared to day 1. The interoccasion variability was lower than interindividual variability for both V(d) and Cl, suggesting that it could be feasible to individualise dosage of 5-FU for subsequent cycles from data obtained in a previous one in an attempt to improve the therapeutic index of colorectal cancer treatment.
Copyright 2003 Wiley-Liss, Inc.