Breath Test for CYP2D6 Activity in Candidates for Tamoxifen Therapy

描述（由申请人提供）：Physical Sciences Inc. (PSI)，沿着我们的研发合作伙伴，儿童慈善医院（CMH）和剑桥同位素实验室公司。(CIL)已经进行了I期研究，成功证明了快速13 C标记的美沙芬（DM）呼气试验评估CYP 2D 6酶活性的可行性。在目前的II期申请中，PSI与马约诊所癌症中心合作，建议进行调查，以确定这种简单的呼吸测试在开始他莫昔芬治疗的乳腺癌患者队列中预测2D 6酶活性的潜在效用。通过评价受试者测量的呼吸试验表型与其内昔芬稳态血浆浓度和内昔芬与N-去甲基他莫昔芬（NDM）代谢物比值的相关性，确定呼吸试验的预测能力。呼气试验结果还将与同一队列中进行的CYP 2D 6基因型单独测定相关。现在有大量的研究表明，接受他莫昔芬治疗的女性中的内昔芬血浆浓度与CYP 2D 6基因型和伴随的强效CYP 2D 6抑制剂高度相关，并可能对他莫昔芬治疗的反应产生影响。此外，初步临床研究（包括我们的马约诊所合作者进行的研究）显示了他莫昔芬的临床结局与CYP 2D 6基因型/表型之间的相关性。与基因分型相比，所提出的表型呼气试验预测受试者对他莫昔芬的反应的潜在优势是：1）与基因分型不同，表型测试可以解释影响患者实际代谢能力的药物-药物和其他体内相互作用，以及2）所提出的表型检测可能有助于解决在基因型类别内观察到的内昔芬浓度的显著受试者间变异性（即使考虑到用药史）。如果成功的话，这项拟议中的研究可能会导致一种非常有用的，基于办公室的测试，用于指导和优化他莫昔芬治疗在乳腺癌患者中的使用。公共卫生相关性：拟议的研究旨在开发一种快速，非侵入性的呼吸测试，可以准确地评估一个人的活动，为一个关键的肝酶参与代谢的各种药物。这些药物的例子包括某些抗抑郁药、抗精神病药、镇痛药和用于乳腺癌治疗的他莫昔芬。从这种基于办公室的测试中获得的信息最终可以使医生根据个人定制药物选择和剂量，从而减少药物不良事件，如毒性反应和不良治疗反应。

DESCRIPTION (provided by applicant): 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.