Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: A validation study
Introduction
The transdermal nicotine patch is the most widely used form of nicotine replacement therapy (NRT) for smoking cessation (West et al., 2001), producing close to a two-fold increase in quit rates compared to placebo (Stead et al., 2008). Yet, only about 1 in 5 smokers who use this NRT quit smoking successfully (Stead et al., 2008). The identification of a pretreatment biomarker test to predict the effectiveness of transdermal nicotine for individual smokers may enable providers to optimize the choice and dose of pharmacotherapy and, in turn, to improve success rates for smoking cessation.
Nicotine, the addictive chemical in tobacco, is metabolized to cotinine and then subsequently to 3′-hydroxycotinine (3-HC) by the cytochrome P450 (CYP) 2A6 enzyme (Nakajima et al., 1996, Messina et al., 1997). The ratio of plasma 3-HC to its precursor cotinine provides a stable measure of individual differences in nicotine metabolism from cigarette smoking that is independent of time since last cigarette (Dempsey et al., 2004, Lea et al., 2006, Mooney et al., 2008). Previously, we reported that a faster nicotine metabolism rate, as indicated by a higher pre-treatment 3-HC/cotinine ratio derived from nicotine from cigarette smoking, predicts lower nicotine concentrations during treatment, more severe cravings to smoke among those abstinent, and lower quit rates with transdermal nicotine (Lerman et al., 2006). In addition, faster metabolizers based on the 3-HC/cotinine ratio also were less likely to quit with behavioral counseling and placebo in a bupropion randomized trial and with counseling provided along with placebo bupropion (Patterson et al., 2008).
The current study was designed to validate the predictive clinical validity of the nicotine metabolite ratio in an independent sample of smokers receiving 8 weeks of 21 mg transdermal nicotine treatment. Such evidence could provide additional proof of concept for the application of this biomarker to personalized tailoring of pharmacotherapy for smoking cessation.
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Participants
Subjects were recruited via advertisements for a free smoking cessation program at an academic setting. Subjects underwent a medical history and physical to confirm eligibility. To be eligible, subjects must have been age 18–65, report smoking > 10 cigarettes/day, and interested in cessation treatment. Female subjects were excluded if they were pregnant, planning a pregnancy, or lactating. Subjects were also excluded if they had a current medical problem for which transdermal nicotine is
Sample characteristics and covariates
The average age of participants was 45 years (SD = 10.3), 55% of the sample was male, more than 90% of the sample had at least a high school diploma or additional education, and 84% of the sample was Caucasian. The average number of cigarettes smoked per day was 21.2 (SD = 9.2), the average number of previous quit attempts was 1.7 (SD = 3.8), and the average FTND score was 5.2 (SD = 2.1). Averages for nicotine metabolite measurements at baseline were as follows: cotinine (269 ng/mL, SD = 117), 3-HC
Discussion
This study validates prior findings of the predictive validity of the 3-HC/cotinine ratio as a marker for successful quitting with 21 mg transdermal NRT (Lerman et al., 2006). Across two independent studies we have demonstrated that the rate of nicotine metabolism, measured by the 3-HC/cotinine ratio, predicts cessation after treatment with the standard 21 mg dose of nicotine patch. While smokers in the upper (faster) quartiles of nicotine metabolism show the expected approximately 30% 8-week
Grant support
This research was supported by a Transdisciplinary Tobacco Use Research Center Grant from the National Cancer Institute and National Institute on Drug Abuse P5084718 (CL), and National Institute on Drug Abuse grants DA02277 (NB) and DA20830 (NB, RFT and CL).
Conflicts of interest
Dr. Lerman has served as a consultant to GlaxoSmithKline, the company that manufactures the nicotine patch used in this study. However, GSK did not provide medication or financial support for this study. Dr. Tyndale is a shareholder and CSO for Nicogen, a company focused on novel smoking cessation approaches. No funding was provided from Nicogen for this study. Dr Benowitz has been a paid consultant to several pharmaceutical companies that market and/or are developing medications for smoking
Acknowledgements
The authors would like to thank the following individuals who participated in the implementation of this research project: Dr. Margaret Rukstalis, Dr. Daniel Heitjan, Angela Pinto, Susan Ware, and Lisa Yu.
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