Overcoming Tramadol Resistance In CYP2D6 Poor Metabolizers

克服 CYP2D6 代谢不良者的曲马多耐药性

• 批准号: 8713969
• 负责人: STUART J KAHN
• 金额: $ 58.31万
• 依托单位: SYNTRIX BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713969
• 关键词: Absence of pain sensation; Adopted; Analgesics; Binding; Caucasians; Caucasoid Race; Clinical Trials; Controlled Clinical Trials; Country; Cross-Over Studies; Cyclic GMP; Cytochrome P-450 CYP2D6; Data; Dose; Drug Formulations; Elements; Funding; Generic Drugs; Genetic Crossing Over; Genotype; Human; Individual; Isoenzymes; Marketing; Metabolic; Modeling; Nociceptive Stimulus; Opiate Addiction; Opioid; Opioid Receptor; Parents; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenotype; Physicians; Plague; Population; Production; Randomized; Resistance; Risk; Sales; Serum; Small Business Innovation Research Grant; Spinal; Tablets; Testing; Tramadol; base; improved; novel; novel therapeutics; pilot trial; public health relevance; research clinical testing

DESCRIPTION (provided by applicant): Tramadol is a widely prescribed analgesic, with over 25 million prescriptions and $565 million in retail sales in 2009, making it among the best selling generic drugs. One of the advantages of tramadol over traditional opioids is its lower risk of opioid dependence, resulting in it having an unscheduled status in the U.S. and other countries. Although its mode of action is not completely understood, its analgesic activity is due to synergy between both the parent drug and the desmethyltramadol (M1) metabolite. The production of M1 and its opioid activity is critically dependent on the polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Approximately 10% of Caucasians have a genotype that results in reduced activity of CYP2D6. These individuals are poor metabolizers (PM) of tramadol, and their M1 serum concentration is significantly less than normal subjects. Several well controlled clinical trials have shown that the analgesic effect of tramadol is decreased or absent in PM subjects who have low CYP2D6 enzymatic activity. The impact of tramadol resistance in 10% of the U.S. population with low or absent CYP2D6 activity is significant, with upwards of a million patients receiving inadequate analgesia from tramadol therapy annually. Further, the need to switch nonresponders to traditional opioids increases their risk of opioid dependence. Within this need- analysis, there exists an opportunity to develop an "improved tramadol" that would be effective in all patients. Such a product would be expected to be quickly adopted by the market and displace existing tramadol sales. Based on extensive single-dose/steady-state human pilot data gathered in the SBIR Phase I segment, we identified a new proprietary M1/Tramadol tablet (SR105) that we hypothesize will overcome tramadol resistance in PMs by directly supplementing these patients with the M1 metabolite that they are incapable of generating on their own. By providing both the M1 metabolite and the parent drug, the entire spectrum of opioid and monoaminergic activity will be restored in subjects with the PM phenotype. This SBIR Phase II proposal aims to develop and finalize the required elements to open an IND with the FDA and to conduct a phase 1, two-segment, randomized cross-over clinical trial in 60 subjects that will begin to test our hypothesis.

描述（由申请人提供）：Tramadol是一种规定的镇痛药，2009年有超过2500万美元的处方和5.65亿美元的零售额，使其成为销量最高的 仿制药。曲马多（Tramadol）比传统阿片类药物的优点之一是其阿片类药物依赖性的较低风险，从而导致其在美国和其他国家的状态外。尽管其作用方式尚未完全理解，但其镇痛活性是由于母体药物和脱甲基甲二醇（M1）代谢产物之间的协同作用。 M1的产生及其阿片类药物的活性严重取决于脱勃斯喹型型的多态同工酶，细胞色素P450 2D6（CYP2D6）。大约10％的高加索人具有基因型，导致CYP2D6的活性降低。这些个体是曲马多代谢剂（PM），其M1血清浓度明显小于正常受试者。几项对照良好的临床试验表明，在CYP2D6酶活性较低的PM受试者中，曲马多的镇痛作用降低或不存在。曲马多（Tramadol）耐药性在10％的美国人群中，CYP2D6活性较低或缺乏曲马多人群，每年有超过一百万的患者接受曲马多治疗的镇痛不足。此外，将无反应者转换为传统阿片类药物的需求增加了其阿片类药物依赖性的风险。在这种需求分析中，存在机会开发“改善的曲马多”，这对所有患者都是有效的。预计这种产品将被市场迅速采用，并取代现有的曲马多销售。基于在SBIR I期细分市场中收集的广泛的单剂量/稳态人体试验数据，我们确定了一种新的专有M1/Tramadol片剂（SR105），我们假设我们将通过直接补充这些M1代谢物的患者来克服PMS中的曲马多抗体，从而可以自有产生M1代谢物。通过提供M1代谢产物和母体药物，将在患有PM表型的受试者中恢复阿片类药物和单胺能活性的整个光谱。该SBIR II期建议旨在开发和最终确定所需的要素，以使用FDA打开IND，并在60名受试者中进行1阶段，两段，随机的跨界临床试验，这些受试者将开始检验我们的假设。