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Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6).

ABSTRACT: BACKGROUND AND AIMS:Evidence suggests that both the nicotinic receptor ?5 subunit (CHRNA5) and Cytochrome P450 2A6 (CYP2A6) genotypes influence smoking cessation success and response to pharmacotherapy. We examine the effect of CYP2A6 genotype on smoking cessation success and response to cessation pharmacotherapy, and combine these effects with those of CHRNA5 genotypes. DESIGN:Placebo-controlled randomized smoking cessation trial. SETTING:Ambulatory care facility in Wisconsin, USA. PARTICIPANTS:Smokers (n?=?709) of European ancestry were randomized to placebo, bupropion, nicotine replacement therapy or combined bupropion and nicotine replacement therapy. MEASUREMENTS:Survival analysis was used to model time to relapse using nicotine metabolism derived from CYP2A6 genotype-based estimates. Slow metabolism is defined as the lowest quartile of estimated metabolic function. FINDINGS:CYP2A6-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, P?=?0.0075], with pharmacotherapy significantly slowing relapse in fast (HR?=?0.39, 95% CI?=?0.28-0.55, P?=?1.97?×?10(-8)), but not slow metabolizers (HR?=?1.09, 95% CI?=?0.55-2.17, P?=?0.80). Further, only the effect of nicotine replacement, and not bupropion, varies with CYP2A6-defined metabolic function. The effect of nicotine replacement on continuous abstinence is moderated by the combined genetic risks from CYP2A6 and CHRNA5 (Wald?=?7.44, d.f.?=?1, P?=?0.0064). CONCLUSIONS:Nicotine replacement therapy is effective among individuals with fast, but not slow, CYP2A6-defined nicotine metabolism. The effect of bupropion on relapse likelihood is unlikely to be affected by nicotine metabolism as estimated from CYP2A6 genotype. The variation in treatment responses among smokers with genes may guide future personalized smoking cessation interventions.

SUBMITTER: Chen LS

PROVIDER: S-EPMC3946972 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6).

Chen Li-Shiun LS Bloom A Joseph AJ Baker Timothy B TB Smith Stevens S SS Piper Megan E ME Martinez Maribel M Saccone Nancy N Hatsukami Dorothy D Goate Alison A Bierut Laura L

Addiction (Abingdon, England) 20131111 1

<h4>Background and aims</h4>Evidence suggests that both the nicotinic receptor α5 subunit (CHRNA5) and Cytochrome P450 2A6 (CYP2A6) genotypes influence smoking cessation success and response to pharmacotherapy. We examine the effect of CYP2A6 genotype on smoking cessation success and response to cessation pharmacotherapy, and combine these effects with those of CHRNA5 genotypes.<h4>Design</h4>Placebo-controlled randomized smoking cessation trial.<h4>Setting</h4>Ambulatory care facility in Wiscon ...[more]

PMID: 24033696

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Project description:IntroductionGenetic variation in Cytochrome P450 2A6 (CYP2A6), the major nicotine metabolizing enzyme, is associated with nicotine dependence and smoking cessation. Nicotine dependence severity also predicts smoking cessation. Our goals were to determine how CYP2A6 variation and nicotine dependence alter smoking cessation, and whether dependence could refine CYP2A6-based treatment recommendations.Aims and methodsAdult smokers treated for 12 weeks with placebo, nicotine patch, or varenicline (NCT01314001) were grouped as CYP2A6 normal (n = 567) or slow (n = 432) nicotine metabolizers based on a CYP2A6 weighted genetic risk score. Fagerström test for nicotine dependence scores were measured at baseline and biochemically verified smoking cessation was assessed at end of treatment.ResultsDependence neither mediated nor moderated an association between CYP2A6 variation and smoking cessation overall, within any treatment arm, or after stratifying by ancestry (n = 591 European, n = 408 African ancestry) or sex (n = 444 women, n = 555 men). In within-treatment analyses, the mediation effect odds ratio (OR) ranged from 0.95 to 1.00 and the bias-corrected 95% confidence interval contained 1. Moderation (i.e. interaction) effect ORs ranged from 0.88 to 1.61 (p = .397-.828). For CYP2A6 normal metabolizers, quit rates on varenicline were similar for those with high (41.1%) and low (43.4%) dependence, while quit rates were lower for those with high versus low dependence on both patch (16.5 vs. 29.7%) and placebo (8.9 vs. 18.5%). CYP2A6 slow metabolizers with high versus low dependence had lower quit rates in all three treatment arms.ConclusionsAlthough nicotine dependence severity neither mediated nor moderated CYP2A6 associations with smoking cessation, incorporating information on dependence may optimize the choice of smoking cessation treatment aid in CYP2A6 normal and slow metabolizers.ImplicationsVariation in CYP2A6 and nicotine dependence severity alter smoking cessation success. Our findings suggest that while nicotine dependence severity is unlikely to mediate or moderate CYP2A6 associations with cessation, incorporating patient information on both CYP2A6 and nicotine dependence severity may lead to improved smoking cessation strategies.

Project description:Introduction:Varenicline doubles cessation over nicotine replacement therapy (NRT) patch for "normal," but not "slow," nicotine metabolizers, as assessed by the nicotine metabolite ratio (NMR). Metabolism-informed care (MIC) could improve outcomes by matching normal metabolizers with non-nicotine medication (e.g., varenicline) and slow metabolizers with NRT patch. Methods:We conducted a feasibility randomized controlled trial of MIC versus guideline based care (GBC) among 81 outpatient adult daily smokers with medical comorbidity. Participants reported perceptions of MIC, underwent blood draw for NMR, and received expert cessation counseling. For MIC participants, medication selection was informed by NMR result (normal (?0.31) vs. slow (< 0.31)). The primary outcome was MIC feasibility, reflected by attitudes toward MIC and by match rates between NMR and medication. Secondary endpoints (cessation confidence, medication use, smoking status) were assessed over 6 months to inform future studies. Results:Participants were median age 53 years, 46% female, 28% black, and ~90% endorsed MIC. Despite high varenicline prescription rates (~60%) in both arms, NMR-medication matching was higher in MIC (84%) versus GBC (58%) participants (p=0.02); unadjusted odds ratio (OR) 3.67, 95% confidence interval [1.33, 11.00; p-value=0.02]. Secondary endpoints were similar at 1, 3, and 6 months. Conclusions:MIC, an NMR-based precision approach to smoking cessation, was acceptable to 90% of smokers and improved NMR-medication match rates more than 3-fold compared to GBC, even with generally high use of varenicline. These data support the feasibility of MIC, which could maximize efficacy of smoking cessation medication while minimizing side effects and cost. Implications:Among treatment-seeking daily smokers with medical comorbidity, most viewed metabolism-informed care (MIC), guided by the nicotine metabolism ratio (NMR), favorably, and were willing to accept MIC-guided medication. Compared to GBC participants (58%), more MIC participants (84%) were prescribed NMR-matched medication (i.e., normal metabolizers received varenicline; slow metabolizers received NRT patch). MIC increased the odds of optimized matching between NMR and medication more than 3-fold over GBC. Because the number needed to treat (NNT) to help one normal metabolizer quit smoking is only 4.9 for varenicline versus 26 for patch, broad implementation of MIC will improve drug efficacy in normal metabolizers as well as minimize side effects in slow metabolizers.

Dataset Information

Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6).

Publications

Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6).

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