Overcoming Tramadol Resistance In CYP2D6 Poor Metabolizers

描述(申请人提供)：曲马多是一种广泛使用的止痛药，2009年有超过2500万张处方和5.65亿美元的零售额，使其成为最畅销的药物之一 仿制药。与传统阿片类药物相比，曲马多的优势之一是它对阿片类药物依赖的风险较低，导致它在美国和其他国家的计划外地位。虽然其作用机制尚不完全清楚，但其镇痛活性是由于母药和去甲基曲马多(M1)代谢物之间的协同作用。M1的产生及其阿片类药物的活性严重依赖于debrisquine类型的细胞色素P450 2D6(CYP2D6)的多态同工酶。大约10%的高加索人有一种导致CYP2D6活性降低的基因。这些人是曲马多的低代谢者(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CYP2D6酶活性低的PM患者中，曲马多的止痛作用减弱或消失。在美国10%的低活性或缺乏CYP2D6活性的人群中，曲马多耐药的影响是显著的，每年有100多万患者接受曲马多治疗的止痛不足。此外，将无反应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。在这个需求分析中，有机会开发一种对所有患者都有效的“改良曲马多”。这样的产品预计将很快被市场采用，并取代现有的曲马多销售。基于在SBIR第一阶段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利M1/曲马多片(SR105)，我们假设该药将通过直接向这些患者补充他们自己无法产生的M1代谢物来克服PM对曲马多的耐药性。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阿片类药物和单胺能活性的整个光谱。这项SBIR第二阶段的提案旨在开发和最终确定向FDA开放IND所需的要素，并在60名受试者中进行一项第一阶段、两段式随机交叉临床试验，该试验将开始检验我们的假设。

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.