Assessment of High Dose Transdermal Nicotine for Fast Metabolizers of Nicotine

描述（由申请人提供）：治疗尼古丁依赖的新方法仍然是优先考虑的。透皮尼古丁贴片是最广泛使用的烟草依赖治疗形式，但只有约五分之一的吸烟者使用这种治疗方法戒烟。可能导致对透皮尼古丁反应不佳的一个因素是尼古丁代谢率的个体差异，这可以通过唾液中3'羟基可替宁（3-HC）与其前体可替宁的比例来测量。两项经皮尼古丁的临床试验表明，3-HC/可替宁比值可以预测对经皮尼古丁的反应，即尼古丁代谢快的人（3-HC/可替宁比值高）的戒烟率较低，而尼古丁代谢慢的人戒烟率较低。在这些试验中的戒烟者中，3- HC/可替宁比值也预测透皮尼古丁的治疗水平，尼古丁代谢快的人尼古丁含量较低。因此，快速代谢尼古丁的人可能需要更高的尼古丁剂量才能获得与缓慢代谢尼古丁的人相同的经皮尼古丁治疗效果。迄今为止，临床试验表明，与标准剂量的透皮尼古丁（21毫克）相比，更高剂量（42毫克）对戒烟率没有显著影响。然而，没有一项高剂量透皮尼古丁的试验考虑到尼古丁代谢率的个体差异。因此，作为开展一项全面的随机临床试验的初步步骤，我们建议首次评估高剂量透皮尼古丁（相对于标准剂量）对尼古丁快速代谢者（即3-HC/可替宁比例分布的上四分位数）的有效性。我们只选择快速代谢的尼古丁进行试验，因为：1)缓慢代谢的尼古丁在标准透皮尼古丁上表现出很高的戒烟率，并且可能在高剂量时出现不良反应；2)作为R21应用的“概念验证”，我们的主要目标是测试高剂量尼古丁是否会增加尼古丁快速代谢者的戒烟率。具体来说，100名尼古丁快速代谢的吸烟者将接受咨询，并将随机分为：1)标准（1 X 21mg贴片和1 X安慰剂贴片），或2)高剂量（2 X 21mg贴片）透皮尼古丁。主要终点是8周治疗后经生化验证的7天点患病率停止。还将评估不同研究条件下贴片相关副作用和透皮尼古丁效应介质（如尼古丁水平、戒断）的差异。最终，这条研究路线希望提供必要的证据，将3-HC/可替宁比率的研究转化为治疗烟草依赖的临床实践。具体来说，本研究可能表明，通过提供标准贴片剂量的尼古丁慢代谢剂和高剂量透皮尼古丁的尼古丁快代谢剂，尼古丁代谢率的测量可以最大限度地提高透皮尼古丁的治疗效果。由于这些人患肺癌的风险增加，找到一种有效的治疗方法来治疗尼古丁的快速代谢者也很重要。

DESCRIPTION (provided by applicant): Novel approaches to treating nicotine dependence remain a priority. The transdermal nicotine patch is the most widely used form of tobacco dependence treatment, but only ~1 in 5 smokers who use this treatment achieve cessation. One factor that may contribute to a poor response to transdermal nicotine is inter-individual variability in the rate of nicotine metabolism, which can be measured in saliva by the ratio of 3'hydroxycotinine (3-HC) to its precursor cotinine. Two clinical trials with transdermal nicotine have shown that the 3-HC/cotinine ratio predicts response to transdermal nicotine such that faster metabolizers of nicotine (higher 3-HC/cotinine ratios) have lower quit rates, vs. slower nicotine metabolizers. Among abstainers in these trials, the 3- HC/cotinine ratio also predicts therapeutic levels of nicotine on transdermal nicotine, with faster metabolizers of nicotine exhibiting lower nicotine. Thus, faster metabolizers of nicotine may require higher nicotine doses to achieve the same therapeutic benefit from transdermal nicotine as do slow nicotine metabolizers. To date, clinical trials have shown that, compared to the standard dose of transdermal nicotine (21mg), higher doses (42mg) have no significant effect on quit rates. However, no trial of high dose transdermal nicotine considered inter-individual variability in the rate of nicotine metabolism. Thus, as a preliminary step toward conducting a fully-powered, randomized clinical trial to assess standard vs. high dose transdermal nicotine for slow vs. fast metabolizers of nicotine, we propose to evaluate, for the first time, the efficacy of high-dose transdermal nicotine (vs. standard dose) among fast metabolizers of nicotine (i.e., upper quartile of the 3-HC/cotinine ratio distribution). We chose only fast metabolizers of nicotine for this trial since: 1) slow metabolizers of nicotine exhibit high quit rates on standard transdermal nicotine and may experience adverse effects from higher doses; and 2) as a "proof of concept" R21 application, our primary objective is to test whether high doses of nicotine increase quit rates among fast metabolizers of nicotine. Specifically, 100 smokers who are fast metabolizers of nicotine will receive counseling and will be randomized to: 1) standard (1 X 21mg patch and 1 X placebo patch), or 2) high dose (2 x 21mg patches) transdermal nicotine. The primary outcome is biochemically-verified 7-day point prevalence cessation after 8 weeks of treatment. Differences in patch-related side effects and mediators of transdermal nicotine effects (e.g., nicotine levels, withdrawal) across the study conditions will also be assessed. Ultimately, this line of research hopes to provide the evidence necessary to translate research on the 3-HC/cotinine ratio to clinical practice for the treatment of tobacco dependence. Specifically, this research may show that a measure of nicotine metabolism rate could be used to maximize the therapeutic benefits of transdermal nicotine by providing slow metabolizers of nicotine with a standard patch dose and fast metabolizers of nicotine with high dose transdermal nicotine. Identifying an effective treatment for faster metabolizers of nicotine is also critical since these individuals are at increased risk for lung cancer. PUBLIC HEALTH RELEVANCE: Unfortunately, we still need to assess and identify novel ways to help people quit smoking. Differences between people in terms of how fast they metabolize nicotine influences response to transdermal nicotine patches, the most popular nicotine dependence treatment, and it affects plasma levels of nicotine from treatment. These studies suggest that fast metabolizers of nicotine may show better quit rates if they receive higher doses of transdermal nicotine. This preliminary study is designed to assess, for the first time, whether fast nicotine metabolizers show higher quit rates if given high dose transdermal nicotine, vs. standard dose. The study findings may help to support a subsequent large trial to assess standard vs. high dose transdermal nicotine for slow vs. fast metabolizers of nicotine, which may lead to a more personalized approach to treating nicotine dependence using the nicotine patch to improve therapeutic benefits of transdermal nicotine.