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RESEARCH PRODUCT

A Bayesian Method for Predicting 5‐Fluorouracil Pharmacokinetic Parameters Following Short‐Term Infusion in Patients With Colorectal Cancer

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Abstract 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. © 2003 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:1155–1165, 2003