Overcoming Tramadol Resistance In CYP2D6 Poor Metabolizers

描述（由申请人提供）：曲马多是一种广泛使用的止痛药，2009年的处方量超过2500万张，零售额为5.65亿美元，是最畅销的药物之一 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处于非计划状态。虽然其作用方式尚未完全了解，但其镇痛活性是由于母体药物和去甲基曲马多（M1）代谢产物之间的协同作用。M1的产生及其阿片活性严重依赖于异喹胍型细胞色素P450 2D 6（CYP 2D 6）的多态性同工酶。大约10%的高加索人具有导致CYP 2D 6活性降低的基因型。这些人是曲马多的弱代谢者（PM），他们的M1血清浓度显著低于正常受试者。几项对照良好的临床试验表明，在CYP 2D 6酶活性低的PM受试者中，曲马多的镇痛作用降低或不存在。在10%的CYP 2D 6活性低或缺乏的美国人群中，曲马多耐药的影响是显著的，每年有超过100万患者接受曲马多治疗的镇痛不足。此外，将无应答者转换为传统阿片类药物的需要增加了他们对阿片类药物依赖的风险。在这种需求分析中，存在着开发对所有患者有效的“改进的曲马多”的机会。预计这种产品将很快被市场采用，并取代现有的曲马多销售。基于SBIR I期部分收集的大量单次给药/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（SR 105），我们假设该片剂将通过直接向PM患者补充他们无法自行产生的M1代谢物来克服PM中的曲马多耐药性。通过提供M1代谢产物和母体药物，具有PM表型的受试者的阿片样物质和单胺能活性的整个谱将恢复。本SBIR II期提案旨在制定并最终确定向FDA开放IND所需的要素，并在60例受试者中开展一项I期、两阶段、随机交叉临床试验，该试验将开始以检验我们的假设。 公共卫生相关性：曲马多是一种广泛使用的止痛药，但10%的美国人口对曲马多的止痛作用有抵抗力。本项目旨在通过开发一种新的治疗方法和相应的I期临床试验来克服曲马多对疼痛药物的耐药性。

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. PUBLIC HEALTH RELEVANCE: Tramadol is a widely prescribed analgesic, but 10% of the U.S. population is resistant to Tramadol analgesic effects. This project aims to overcome Tramadol resistance for pain medication by developing a new therapeutic, and corresponding Phase I clinical trial.