Population pharmacokinetics of adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF)

Despite the success of adjuvant cyclophosphamide, methotrexate (MTX), 5-fluouracil (5-FU) (CMF) treatment for early stage breast cancer, more than 35% of patients die within 5 years of diagnosis. Optimisation of the dose of each component drug may improve survival and reduce toxicity. In this study, the pharmacokinetics of intravenous (i.v.) cyclophosphamide (600 mg/m(2)), MTX (40 mg/m(2)) and 5-FU (600 mg/m(2)) were determined in 46 women, with data on two consecutive courses available for 41 patients. A population analysis using NONMEM was performed to investigate the effect of patient covariates on pharmacokinetics (PK), and to estimate the relative magnitude of interindividual and interoccasion variability. Patient weight had a significant influence on the clearance of cyclophosphamide and on the volume of central compartment for MTX, whose clearance was dependent on renal function. For all three drugs, interoccasion variability was of the same order (20-40%) as that between individuals, suggesting a limited potential for dose-optimisation of this regimen.