Pharmacokinetic considerations in the design of optimal chemotherapeutic regimens for the treatment of breast carcinoma: a comceptual approach.
Pharmacological data are currently available for a number of antineoplastic agents which have shown clinical activity in advanced breast carcincoma. Preclinical data reveal a relationship between therapeutic response and certain pharmacokinetic parameters such as time of effective cytotoxic exposure (Teff) and the product of concentration with time (Cxt). We have attempted to apply human pharmacologic data to get estimates of these parameters for 6 active agents in breast cancer, to relate them to response rates, and to suggest a method for estimating the role of individual drugs in a multidrug combination. The response rates for 6 single agents were obtained from literature review and related to estimates of Teff and Cxt. The Cxt-response relations for single drugs were linear for cyclophosphamide, 5-fluorouracil, and thiotepa; exponential for vincristine; and relatively flat for methotrexate and cytoxine arabinoside. Most Teff values for the active single agents clustered about 15 hr/dose. From the graphs of response rate vs Cxt, the individual contribution of each agent in a combination study was estimated to arrive at a predicted response rate. The predicted response rates for the combination studies correlated with the actual response rates determined in the clinical study, for 6 of 6 nonrandomized studies and for 12 of 14 randomized studies analyzed. In 2 studies, deviations from the predicted response rate were attributed to differences in study design or analysis. There was no correlation between Teff and predicted response rate. Analyses of pharmacokinetic data may be useful to simulate combination chemotherapy studies to predict the effectiveness of clinical trials in breast cancer. Since the pharmacologic data were not obtained for any of the agents in the actual clinical trials done, we can only speculate on the usefulness of this method. We would encourage the prospective collection of this data in future clinical trails.
D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000378:metabolism; D003561:Cytarabine / Q000008:administration & dosage / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008727:Methotrexate / Q000008:administration & dosage / Q000378:metabolism; D012107:Research Design; D014750:Vincristine / Q000008:administration & dosage / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D003561:Cytarabine; D014750:Vincristine; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate