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镇痛药，2007年有18,526,000张处方和281,559,000美元的零售额，使其成为第31位最畅销的仿制药。与传统阿片类药物相比，曲马多的优势之一是其对阿片类药物依赖的风险较低，因此在美国和其他国家具有计划外的地位。虽然其作用方式尚不完全清楚，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的产生及其阿片活性严重依赖于碎片醌型细胞色素P450 2D6 （CYP2D6）的多态性同工酶。大约10%的高加索人具有导致CYP2D6活性降低的基因型。这些个体曲马多代谢不良（PM）， M1血清浓度明显低于正常人。几项对照良好的临床试验表明，曲马多的镇痛作用在CYP2D6酶活性低的PM患者中降低或不存在。在美国10% CYP2D6活性低或缺失的人群中，曲马多耐药性的影响是显著的，超过60万患者可能接受曲马多治疗后镇痛不足。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。在这种需求分析中，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。根据曲马多及其M1代谢物的已知药代动力学和疗效数据，我们假设可以开发一种含有曲马多及其M1代谢物的联合片剂，通过直接补充这些患者自身无法产生的M1代谢物来克服pmms中的曲马多耐药性。通过同时提供M1代谢物和母体药物，阿片类药物和单胺能活性的整个谱将在PM表型的受试者中恢复。基于曲马多已知的治疗指标，我们进一步假设这种联合片剂在正常受试者中也能提供安全有效的镇痛效果。这样的联合片剂将消除患者CYP2D6基因型对曲马多疗效的影响。无需考虑需要曲马多镇痛的患者是否具有CYP2D6 PM基因型，这对医生来说将是一个明显的处方优势。公共卫生相关性：疼痛是影响约1%人口的人类残疾的主要原因。曲马多是一种广泛使用的止痛药，2007年被开了1852.6万次。曲马多的一个重要优点是其对阿片类药物依赖的风险较低。大约10%的高加索人不能使用曲马多，因为他们不能适当地处理这种药物。该项目将开发一种新的、改进的曲马多，它可以被所有人加工，造福于他们。

DESCRIPTION (provided by applicant): Tramadol is a widely prescribed analgesic, with 18,526,000 prescriptions and $281,559,000 in retail sales in 2007, making it the 31st best selling generic drug. 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 600,000 patients potentially receiving inadequate analgesia from tramadol therapy. Further, the need to switch non- responders 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 the known pharmacokinetic and efficacy data for tramadol and its M1 metabolite, we hypothesize that a combination tablet comprising tramadol and its M1 metabolite can be developed that 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. Based on the known therapeutic index of tramadol, we further hypothesize that such a combination tablet will provide safe and effective analgesia in normal subjects as well. Such a combination tablet will obviate the influence of a patient's CYP2D6 genotype on tramadol efficacy. Not having to consider if a patient who requires analgesia with tramadol has the the CYP2D6 PM genotype will be a clear prescribing advantage to physicians. PUBLIC HEALTH RELEVANCE: Pain is a leading cause of human disability effecting ~1% of the population. Tramadol is a widely prescribed pain medication that was prescribed 18,526,000 times in 2007. An important advantage of tramadol is its lower risk of opioid dependence. Approximately 10% of Caucasians can not use tramadol because they fail to process the drug appropriately. This project will develop a new, improved tramadol that can be processed by all people for their benefit.