Physical Sciences Inc. (PSI), along with our R&D collaborators, Children's Mercy Hospital (CMH) and Cambridge Isotope Laboratories, Inc. (CIL), have performed Phase I investigations successfully demonstrating the feasibility of a rapid, 13C labeled dextromethorphan (DM) breath test to assess CYP2D6 enzyme activity. Under the current Phase II application, PSI, in collaboration with the Mayo Clinic Cancer Center, proposes to carry out investigations to establish the potential utility of this simple breath test for predicting 2D6 enzyme activity in a cohort of breast cancer patients initiating tamoxifen therapy. The predictive capability of the breath test will be established by evaluating the correlation of the subjects' measured breath test phenotypes with their steady state plasma concentrations of endoxifen and metabolite ratios of endoxifen to N-Desmethyltamoxifen (NDM). Breath test results will also be correlated with separate determinations of CYP2D6 genotype made in the same cohort. There now exists a large body of research that shows that endoxifen plasma concentrations in women undergoing tamoxifen therapy are highly associated with CYP2D6 genotype and concomitant potent CYP2D6 inhibitors and may have an impact on the response to tamoxifen therapy. Furthermore, preliminary clinical studies (including those performed by our Mayo Clinic collaborators) have shown associations between clinical outcomes of tamoxifen and CYP2D6 genotype/phenotype. The potential advantages of the proposed phenotyping breath test over genotyping to predict a subject's response to tamoxifen are: 1) unlike genotyping, the phenotyping test can account for drug-drug and other in vivo interactions affecting a patient's actual metabolic capacity, and 2) the proposed phenotyping test may help resolve the significant intersubject variability of endoxifen concentrations that has been observed within genotype classes (even when accounting for medication history). If successful, the proposed research could lead to a very useful, office- based test for guiding and optimizing the use of tamoxifen therapy in breast cancer patients. PUBLIC HEALTH RELEVANC:The proposed research seeks to develop a rapid, non-invasive breath test that can accurately assess an individual's activity for a key liver enzyme involved in the metabolism of a wide range of drugs. Examples of these drugs include certain anti-depressants, anti-psychotics, analgesics, and tamoxifen for breast cancer therapy. The information gained from this office-based test could ultimately enable physicians to tailor drug selection and dosing according to the individual, thereby reducing adverse drug events such as toxic reactions and poor therapeutic response. ? ? ?
| Safgren, Stephanie L; Suman, Vera J; Kosel, Matthew L et al. (2015) Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen. Pharmacogenet Genomics 25:157-63 |
