Chemotherapeutic dosing has traditionally been empiric, with all patients receiving the same dose adjusted for body surface area (BSA). Unfortunately, while this may be adequate for the average person, it can be inappropriate for the majority of patients. Pharmacokinetic and pharmacodynamic factors are key components contributing to drug toxicities. Variations in metabolic enzyme activity have been shown to be responsible for toxicity in a number of anticancer agents including amonafide. Amonafide showed significant promise in treating metastatic breast cancer in the 1990's. However, unpredictable toxicity produced by N-acetylation limited development. We and others have previously developed dosing nomograms for amonafide in an effort to both reduce toxicity and increase response. In our phase I proposal, we developed a rapid method for NAT2 phenotyping. Here in phase II, we will use this method to develop a new acetylator-based dosing nomogram with individualized dosing levels aimed at the treatment of refractory breast cancer. We will refine our theoretical nomogram by adjusting dosing levels on the basis of myelosuppression. This adjusted dosing nomogram will then be used to select amonafide doses in an 80 patient cohort. Our goal is to demonstrate that our acetylator-based dosing nomogram will minimize variability in toxicity and increase the probability of positive therapeutic outcome.
