Toward Personalized Therapy for Smoking Cessation: A Randomized Placebo-controlled Trial of Bupropion

Abstract

We examined whether a pretreatment phenotypic marker of nicotine metabolism rate (NMR) predicts successful smoking cessation with bupropion. Smokers (N = 414) were tested for pretreatment NMR, based on the ratio of 3′-hydroxycotinine/ cotinine derived during smoking, before entering a placebocontrolled randomized trial of bupropion plus counseling. At the end of the 10-week treatment phase, slow metabolizers (1st NMR quartile) had equivalent quit rates with placebo or bupropion (32%). Fast metabolizers (4th NMR quartile) had low quit rates with placebo (10%), and these were enhanced significantly by bupropion (34%). Smokers in the 2nd quartile (placebo: 25%, bupropion: 30%) and the 3rd quartile (placebo: 20%, bupropion: 30%) did not benefit significantly from bupropion. At the 6-month follow-up, the relationship between the NMR and quitting remained similar, but was no longer statistically significant. A pretreatment assessment of NMR may identify smokers who are most and least likely to benefit from treatment with bupropion for smoking cessation.Personalized medicine, in which therapies are delivered to individual patients on the basis of pretreatment biological markers, is emerging as a new model of healthcare delivery. 1,2 In the area of tobacco dependence treatment, genetic variants in nicotinemetabolizing enzymes are plausible candidates for prediction of therapeutic response. 3,4 Nicotine is metabolized to cotinine (COT), predominantly by the liver enzyme cytochrome P450 (CYP) 2A6; 5,6 COT is further metabolized to trans-3ʹ-hydroxycotinine (3HC) by the same enzyme. 5 Consistent with the premise that faster inactivation and elimination of nicotine lead to higher rates of smoking so as to maintain nicotine levels in the system, reproducible associations of CYP2A6 genotype with smoking behavior have been reported. 3,[7][8][9] The ratio of the levels of 3HC/COT arising from cigarette smoking, as measured in plasma, saliva, or urine, is associated with the CYP2A6 genotype. 3,10,11 This phenotype measure is highly reproducible and independent of time elapsed since the last cigarette. 12-14 Further, the ratio is strongly correlated with plasma nicotine levels and nicotine clearance. 10,14-16 Consistent with these genetic and pharmacokinetic data, we have reported that the nicotine metabolite ratio predicts successful quitting of smoking with the use of transdermal nicotine. 16 In this earlier investigation, the odds of achieving smoking cessation with transdermal nicotine therapy were reduced by 30% with each increasing quartile of the nicotine metabolite ratio. Faster metabolizers of nicotine were less successful in quitting than slower metabolizers and also had lower plasma levels of nicotine during treatment and stronger cravings to smoke.In order to extend this line of research on the role of NMR in achieving success in smoking cessation, we examined the predictive clinical validity of the 3HC/COT ratio within a double-blind placebo-controlled pharmacogenetic clinical trial of bupropion efficacy. [17][18][19] ...

Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine

“…In another clinical trial that tested the efficacy of bupropion for smoking cessation, smokers in the fourth NMR quartile (faster metabolizers) had poor smoking cessation rates if they were assigned the placebo treatment. However, bupropion offset the relapse liability among high NMR smokers (Patterson et al, 2008). Overall, these findings are consistent with the idea that smokers who rapidly metabolize nicotine might be more dependent and have greater difficulty with smoking cessation.…”

“…However, the groups did not differ with respect to overall nicotine withdrawal severity as assessed by the MNWS. As mentioned above, previous studies have found that smokers with high NMR had greater nicotine withdrawal severity and craving for cigarettes Rubinstein et al, 2008), although others did not find an association between NMR and craving or withdrawal (Patterson et al, 2008;Schnoll et al, 2009). The reasons for these conflicting findings remain to be determined.…”

Pharmacokinetic and Pharmacodynamics Studies of Nicotine After Oral Administration in Mice: Effects of Methoxsalen, a CYP2A5/6 Inhibitor

“…However most people in these ethnic groups are not full poor metabolizers, with both alleles being fully null, rather they range from slow to intermediate, to normal, to fast nicotine metabolizers (Ho et al, 2009;Malaiyandi et al, 2005;). Thus, as people with the slowest rates of nicotine metabolism have the best quit rates in both placebo and nicotine replacement therapies (Ho et al, 2009;Lerman et al, 2006Lerman et al, , 2010Patterson et al, 2008;Ray et al, 2009), it is possible that slowing nicotine metabolism using inhibitors, along with nicotine, will combine the two effects observed in placebo and NRT treatment arms to increase the smoking cessation rates (Sellers et al, 2000;Tyndale et al, 1999).…”

Reduced-Nicotine Cigarettes in Young Smokers: Impact of Nicotine Metabolism on Nicotine Dose Effects

“…When smokers were categorized as normal or slow metabolizers on the basis of an NMR criterion, normal metabolizers (⩾0.35) smoked more cigarettes/day (Chenoweth et al, 2014), but slow metabolizers (o0.31) had a greater likelihood of 1-week abstinence from smoking (Chenoweth et al, 2014). When smokers were divided into quartiles based on NMR, the fastest metabolizers had a greater likelihood of abstinence from smoking with bupropion treatment than the slowest metabolizers (Patterson et al, 2008). According to the same quartile system, the slowest metabolizers had lower nicotine dependence, reported less cigarette craving following overnight abstinence, and less drug liking after intravenous nicotine compared to the fastest metabolizers (Sofuoglu et al, 2012).…”