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A genetically informed biomarker of nicotine clearance has been developed, formed using the ratio of 2 nicotine metabolites derived from smoking (3’hydroxycotinine [3HC]/cotinine), referred to as the nicotine metabolite ratio (NMR). The NMR is a valid marker of CYP2A6 variants, which influence nicotine metabolism, for various ethnic groups (West et al., 2011), and captures environmental influences on nicotine clearance as well (e.g., age, hormonal factors, race, gender, and smoking itself; Dempsey et al., 2004; Benowitz et al., 2009; Schnoll et al., 2014). The NMR has strong test-retest reliability, independence from time-since-last-cigarette, and replication across independent labs (Dempsey et al., 2004; Benowitz et al., 2009; Hamilton et al., 2015; Lea et al., 2006; Mooney et al., 2008; Tanner et al., 2015).

We have examined the NMR to personalize treatment for nicotine dependence in 6 independent studies, including, most recently, in a multi-site, prospectively stratified, double-blind randomized clinical trial. Collectively, these studies support a personalized treatment model for maximizing treatment response and minimizing treatment side effects: providing slow metabolizers of nicotine with the nicotine patch and fast metabolizers of nicotine with varenicline (Ho et al., 2009; Kaufmann et al., 2015; Schnoll et al., 2009; Schnoll et al., 2013; Patterson et al., 2009; Tang et al., 2012; Lerman et al., 2015; Lerman et al., 2004). A number- needed-to-treat (NNT) analysis from our recent trial (Lerman et al., 2015) showed that this approach could save costs; among, slow metabolizers of nicotine, there is little difference in the NNT to yield one successful quitter (10.3 for patch vs. 8.1 for varenicline). But, among fast metabolizers of nicotine, the NNT to yield one additional successful quitter is 26 for the nicotine patch vs. 4.9 for varenicline. Cost savings can come from: 1) ensuring that the 1/3 of smokers who are slow metabolizers use nicotine patches (~$125) and not varenicline (~$900), since the quit rates would be equivalent across treatments; and 2) ensuring that the 2/3 of smokers who are fast metabolizers do not waste money on the patch.

One final potential benefit to the NMR is that patients are highly interested in using the NMR to guide treatment and this interest is related to a willingness to use nicotine dependence medications. 78-83% of patients who smoke want to use a genetically-based test if it could improve treatment outcome (Cox et al., 2007; Park et al., 2011) and this interest is associated with a greater willingness to use a medication to quit smoking (Shields et al., 2013) and is increased if information is presented in a healthcare context (Quaak et al., 2012).


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