Factors influencing pharmacokinetics of 5-fluorouracil in cancer patients: a systematic review of population pharmacokinetic models

Purpose 5-Fluorouracil (5-FU) is a traditional chemotherapeutic agent used in the treatment of multiple cancers. This systematic review aimed to summarize the population pharmacokinetic (PopPK) models for both intravenous and pro-drug formulations in cancer patients and to understand the different covariates that affect the pharmacokinetics of 5-FU. Methods the search included studies published from inception to December 2025 in the English language. The non-linear mixed effects model with parametric approach for 5-FU in cancer patients was set as the inclusion criteria. A total of 186 articles were screened for their titles and abstracts from Scopus, PubMed and EMBASE. Out of which 156 were excluded. Out of the 36 articles reviewed, 21 were found suitable for the review. Most of the studies reported a one-compartmental model. Several covariates, including body surface area (BSA), body weight, cancer type, age, gender, UH2/U ratio, serum albumin, creatinine clearance, alkaline phosphatase, total bilirubin, and skeletal muscle index (SMI), influence the pharmacokinetic parameters, including clearance and volume of distribution. Results skeletal muscle index (SMI), body weight, sex, and BSA were the primary covariates influencing the pharmacokinetics of 5-FU. Among the covariates consistently reported as significant, sex was an important determinant of clearance, with males exhibiting higher clearance than females. Increases in body weight and skeletal muscle index were associated with increased clearance, while volume of distribution decreased with lower body surface area. Alkaline phosphatase was reported to have a negative effect on clearance. The substantial interindividual variability observed across studies likely contributes to heterogeneity in reported covariate effects and underscores the need for individualized dosing approaches for 5-FU. Conclusion body weight and sex reported to show clinical significance. This necessitates the need for consideration of these covariates in dosing adjustment. This review summarizes covariates influencing the pharmacokinetics of 5-FU, and reports those identified as significant based on forest plot analysis. This study helps the researchers to perform predictive performance of the reported PopPK models, supporting future model-informed precision dosing strategies for 5-FU-based therapies.