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: 8713969
• 负责人: STUART J KAHN
• 金额: $ 58.31万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713969
• 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2500万张处方和5.65亿美元的零售额，是最畅销的药物之一