VARIABILITY IN THE PHARMACOKINETICS OF CYCLOPHOSPHAMIDE, METHOTREXATEAND 5-FLUOROURACIL IN WOMEN RECEIVING ADJUVANT TREATMENT FOR BREAST-CANCER

A total of 23 women with stage II breast cancer receiving adjuvant cyc lophosphamide, methotrexate and 5-fluorouracil had detailed pharmacoki netic monitoring performed on the first and third courses of therapy. The area under the concentration time curve (AUC) of each of these thr ee drugs varied by a factor of 3-4 among patients. No systematic chang e in pharmacokinetics between the first and third courses was seen for cyclophosphamide, methotrexate or 5-fluorouracil, and the mean AUC fo r each of the three drugs did not change. However, significant intrapa tient variability in drug pharmacokinetics was observed for all three drugs such that the AUC, clearance and half-life in an individual on t he third course could not be reliably predicted from data generated on the first course. On the basis of these results, cyclophosphamide, me thotrexate, and 5-fluorouracil pharmacokinetic data from one treatment would not be useful information from which the doses for subsequent c ourses could be determined.