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: 8517634
• 负责人: STUART J KAHN
• 金额: $ 93.35万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517634
• 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）：曲马多是一种广泛使用的镇痛药，2009 年有超过 2500 万张处方，零售额为 5.65 亿美元，使其成为最畅销的镇痛药之一 仿制药。与传统阿片类药物相比，曲马多的优势之一是其阿片类药物依赖的风险较低，导致其在美国和其他国家具有未列入清单的地位。尽管其作用机制尚不完全清楚，但其镇痛活性是由于母体药物和去甲基曲马多 (M1) 代谢物之间的协同作用。 M1 的产生及其阿片类药物活性主要依赖于异喹啉型细胞色素 P450 2D6 (CYP2D6) 的多态性同工酶。大约 10% 的白种人具有导致 CYP2D6 活性降低的基因型。这些个体是曲马多的不良代谢者（PM），他们的M1血清浓度明显低于正常受试者。几项对照良好的临床试验表明，曲马多的镇痛作用在 CYP2D6 酶活性较低的 PM 受试者中降低或消失。 10% CYP2D6 活性低或缺失的美国人口中，曲马多耐药性的影响是显着的，每年有超过 100 万患者接受曲马多治疗镇痛不足。此外，将无反应者转为传统阿片类药物的需要增加了他们阿片类药物依赖的风险。在这种需求分析中，有机会开发一种对所有患者都有效的“改进的曲马多”。这种产品预计将很快被市场采用并取代现有的曲马多销售。根据 SBIR 第一阶段收集的大量单剂量/稳态人体试验数据，我们确定了一种新的专有 M1/曲马多片剂 (SR105)，我们假设该片剂将通过直接补充 M1 来克服 PM 中的曲马多耐药性它们无法自行产生的代谢物。通过提供 M1 代谢物和母体药物，具有 PM 表型的受试者将恢复整个阿片类药物和单胺能活性。该 SBIR II 期提案旨在开发和最终确定与 FDA 开展 IND 所需的要素，并在 60 名受试者中进行 1 期、两段、随机交叉临床试验，该试验将开始检验我们的假设。