P450 PHENOTYPE AND CHEMOTHERAPY TOXICITY IN THE ELDERLY

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DESCRIPTION (provided by applicant): Interpatient variability in toxic and therapeutic response to chemotherapy remains a major problem in cancer treatment. The long-term goal of this work is to better understand the pharmacologic and pharmacogenetic determinants of this interpatient variability so as to individualize chemotherapy to maximize benefit and minimize toxicity. This is particularly important in older cancer patients, a group that has routinely been excluded from treatment or empirically dose-reduced. The central hypothesis of this research plan is that an individual's activity, or phenotype, of relevant drug metabolizing enzymes, which can be determined at the bedside using carefully selected metabolic "probes," can predict that patient's pharmacokinetics (PK) for certain chemotherapy. Further, the results of these probe-based tests can be incorporated into models to better tailor dosing. The enzymes targeted in this proposal are the cytochromes P450 (CYPs), particularly the enzyme families CYP2 and CYP3, which represent the major pathways for oxidative metabolism of drugs in the liver. There is large interpatient variation in CYP activity. There are known genetic polymorphisms in many CYPs, but CYP genotype and phenotype may not correlate well in patients with cancer. In addition, age-related decline in CYP expression may be a key factor in increased toxicity in this age group. Probe-based tests that assay CYP phenotype have been developed for some of these enzymes but not for others This proposal examines the value of probe tests of CYP activity in predicting pharmacokinetics and toxicity of paclitaxel and vinorelbine. Paclitaxel is principally metabolized by CYP2C8 and CYP3A4, and vinorelbine by CYP3A4. The first trial is a dose escalation study of weekly paclitaxel administered on a novel schedule, which is targeted toward older patients with lung or breast cancer. Detailed pharmacokinetic parameters will be correlated with toxicity. In the second phase of the trial, CYP3A4 activity will be measured using the erythromycin breath test (ERMBT), and a novel probe-based assay for CYP2C8 (rosiglitazone) will be pilot tested. Drug metabolism phenotype will be correlated with paclitaxel clearance and toxicity, and a predictive model will be designed and prospectively validated in future studies. CYP2C8 and CYP3A4 genotype-phenotype correlations will also be explored. In the second clinical trial, age-related decline in CYP3A4 activity and its impact on clearance and neutropenia in patients treated with vinorelbine will be evaluated. Again, predictive models will be designed and genotype-phenotype correlations explored. The research projects described form the core of a five-year career development plan for Dr. Elizabeth Dees, an Assistant Professor in the Division of Hematology/Oncology. Her mentor, Dr. Paul Watkins, is a leader in the field of pharmacogenetics and drug metabolism and is the Director of the GCRC. Co-mentor, Dr. Beverly Mitchell, is the applicant's Division Director and is the Associate Director of Lineberger Comprehensive Cancer Center (LCCC). They propose a combined didactic and clinical research experience utilizing the resources of the LCCC to foster Dr. Dees's development into an independent clinician investigator with expertise in pharmacokinetics and phenotyping drug metabolizing enzymes. They have assembled a carefully selected group of collaborators and advisors to assist in the research projects and Dr. Dees's career development.