Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6). (11th November 2013)

• Record Type: Journal Article
• Authors: Chen, Li‐Shiun; Bloom, A. Joseph; Baker, Timothy B.; Smith, Stevens S.; Piper, Megan E.; Martinez, Maribel; Saccone, Nancy; Hatsukami, Dorothy; Goate, Alison; Bierut, Laura
• Is Part Of: Addiction. Volume 109:Number 1(2014:Jan.)
• Page Start: 128
• Page End: 137
• Publication Date: 2013-11-11
• Subjects: Alcoholism -- Periodicals; Drug addiction -- Periodicals; 616.86
• DOI: 10.1111/add.12353
• Languages: English
• ISSNs: 0965-2140

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="add12353-sec-0001" sec-type="section"> <title>Background and aims</title> <p>Evidence suggests that both the nicotinic receptor α5 subunit (<italic>CHRNA5</italic>) and Cytochrome P450 2A6 (<italic>CYP2A6</italic>) genotypes influence smoking cessation success and response to pharmacotherapy. We examine the effect of <italic>CYP2A6</italic> genotype on smoking cessation success and response to cessation pharmacotherapy, and combine these effects with those of <italic>CHRNA5</italic> genotypes.</p> </sec> <sec id="add12353-sec-0002" sec-type="section"> <title>Design</title> <p>Placebo‐controlled randomized smoking cessation trial.</p> </sec> <sec id="add12353-sec-0003" sec-type="section"> <title>Setting</title> <p>Ambulatory care facility in Wisconsin, USA.</p> </sec> <sec id="add12353-sec-0004" sec-type="section"> <title>Participants</title> <p>Smokers (<italic>n</italic> = 709) of European ancestry were randomized to placebo, bupropion, nicotine replacement therapy or combined bupropion and nicotine replacement therapy.</p> </sec> <sec id="add12353-sec-0005" sec-type="section"> <title>Measurements</title> <p>Survival analysis was used to model time to relapse using nicotine metabolism derived from <italic>CYP2A6</italic> genotype‐based estimates. Slow metabolism is defined as the lowest quartile of estimated metabolic function.</p> </sec> <sec id="add12353-sec-0006" sec-type="section"> <title>Findings</title> <p> <italic>CYP2A6</italic>‐defined nicotine metabolic function moderated the effect of smoking cessation pharmacotherapy on smoking relapse over 90 days [hazard ratio (HR) = 2.81, 95% confidence interval (CI) = 1.32–5.99, <italic>P</italic> = 0.0075], with pharmacotherapy significantly slowing relapse in fast (HR = 0.39, 95% CI = 0.28–0.55, <italic>P</italic> = 1.97 × 10<sup>−8</sup>), but not slow metabolizers (HR = 1.09, 95% CI = 0.55–2.17, <italic>P</italic> = 0.80). Further, only the effect of nicotine replacement, and not bupropion, varies with <italic>CYP2A6</italic>‐defined metabolic function. The effect of nicotine replacement on continuous abstinence is moderated by the combined genetic risks from <italic>CYP2A6</italic> and <italic>CHRNA5</italic> (Wald = 7.44, d.f. = 1, <italic>P</italic> = 0.0064).</p> </sec> <sec id="add12353-sec-0007" sec-type="section"> <title>Conclusions</title> <p>Nicotine replacement therapy is effective among individuals with fast, but not slow, <italic>CYP2A6</italic>‐defined nicotine metabolism. The effect of bupropion on relapse likelihood is unlikely to be affected by nicotine metabolism as estimated from <italic>CYP2A6</italic> genotype. The variation in treatment responses among smokers with genes may guide future personalized smoking cessation interventions.</p> </sec> </abstract>