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，2007年有18,526,000张处方和281,559,000美元的零售额，使其在最畅销的仿制药中排名第31位。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。一些经过良好控制的临床试验表明，在CYP2D6酶活性较低的PM患者中，曲马多的止痛作用减弱或消失。在美国10%的细胞色素P450 2 D6活性低或缺乏的人群中，曲马多耐药的影响是显著的，超过60万名患者可能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依赖阿片类药物的风险。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。根据已知的曲马多及其M1代谢物的药代动力学和疗效数据，我们假设可以开发一种包含曲马多及其M1代谢物的组合片，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PMS中的曲马多耐药性。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。根据已知的曲马多的治疗指标，我们进一步假设，这种复合片也将在正常受试者中提供安全有效的止痛。这样的复合片将消除患者的CYP2D6基因对曲马多疗效的影响。对于医生来说，不必考虑需要曲马多止痛的患者是否具有CYP2D6 PM基因，这将是一个明显的处方优势。公共卫生相关性：疼痛是人类残疾的主要原因，影响到约1%的人口。曲马多是一种广泛开出的止痛药，2007年开了18,526,000次。曲马多的一个重要优势是其较低的阿片依赖风险。大约10%的高加索人不能使用曲马多，因为他们没有适当地处理药物。这个项目将开发一种新的，改进的曲马多，可以被所有人加工，为他们的利益。

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.