Abstract
This summary outlines the evidence base for using a genetically informed biomarker to tailor smoking cessation treatment. This marker represents the rate of CYP2A6-mediated nicotine clearance, and is measured using the ratio of the nicotine metabolites derived from nicotine from smoking (3'hydroxycotinine [3HC]/cotinine), referred to as the nicotine metabolite ratio or NMR. The NMR has been associated retrospectively with the ability to quit smoking and differential response to nicotine dependence therapy in multiple independent clinical trials. We first examined the NMR in an open label trial of transdermal nicotine patch versus nicotine nasal spray. In the patch condition, slow metabolizers (the lowest quartile of the NMR) had significantly higher quit rates than normal metabolizers (2nd to 4th quartiles of the NMR) at the end of 8 weeks of treatment and at 6-month follow up, even after controlling for baseline cigarettes per day and level of nicotine dependence. No such relationship was observed among smokers who received nicotine nasal spray, presumably because they titrated their dose of treatment (and nicotine) based on their CYP2A6-mediated level of nicotine metabolism. Importantly, this relationship of pretreatment NMR (based on smoking) to quit rates with nicotine patch has been validated in an independent trial. Further, a double-blind trial of bupropion versus placebo established a significant NMR-by-treatment interaction; specifically, slow nicotine metabolizers had high quit rates on placebo, which were not enhanced further by the non-nicotine medication bupropion. In contrast, normal nicotine metabolizers performed poorly on placebo, but well on bupropion. Thus, convergent evidence across multiple independent clinical trials supports an association of the NMR with smoking cessation and response to treatments for nicotine dependence. These effects are significant beyond the effects of standard pretreatment clinical measures (e.g., baseline smoking rate, level of nicotine dependence). These data suggest that slow nicotine metabolizers respond well to placebo/behavioral counseling alone and benefit substantially from transdermal nicotine patch, whereas normal nicotine metabolizers achieve little benefit from behavioral counseling alone or nicotine patch, but respond well to non-nicotine medications. To translate these findings to clinical practice, we are initiating a large prospective stratified pharmacogenomic trial that will evaluate the use of the NMR to optimize treatments for nicotine dependence.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):PL01-06.
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