Breath Test for CYP2D6 Activity in Candidates for Tamoxifen Therapy

描述(由申请人提供)：物理科学公司(PSI)与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)已经成功地进行了I期研究，证明了快速、13C标记的右美沙芬(DM)呼气测试用于评估CYP2D6酶活性的可行性。在目前的第二阶段应用中，PSI与梅奥临床癌症中心合作，提议开展调查，以确定这种简单的呼气测试在预测一组开始接受他莫昔芬治疗的乳腺癌患者中的2D6酶活性的潜在效用。呼气试验的预测能力将通过评估受试者所测量的呼气试验表型与其稳态血浆内多昔芬浓度以及内多昔芬与N-去甲基他莫昔芬(NDM)代谢物比率的相关性来建立。呼气测试的结果也将与同一队列中进行的不同的CYP2D6基因检测相关联。现在有大量研究表明，接受他莫昔芬治疗的女性的内多昔芬血药浓度与CYP2D6基因和伴随的强大的CYP2D6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，初步的临床研究(包括我们的梅奥诊所合作者进行的研究)已经表明，他莫昔芬的临床结果与CYP2D6基因/表型之间存在关联。与基因分型相比，建议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)建议的表型测试可能有助于解决在基因类别内观察到的Enoxifen浓度的显著对象间变异性(即使考虑了服药史)。如果成功，这项拟议的研究可能会导致一种非常有用的、以办公室为基础的测试，以指导和优化乳腺癌患者使用他莫昔芬治疗。公共卫生报告：这项拟议的研究旨在开发一种快速、非侵入性的呼气测试，可以准确地评估一个人的一种关键肝酶的活动，这种酶与多种药物的新陈代谢有关。这些药物的例子包括某些抗抑郁药、抗精神病药物、止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能够根据个人情况量身定做药物选择和剂量，从而减少毒性反应和治疗反应差等不良药物事件。

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.