Association of nicotine metabolism and sex with relapse following varenicline and nicotine replacement therapy.

Abstract

Nicotine is metabolized into cotinine and then into trans-3'-hydroxycotinine, mainly by cytochrome P450 2A6. Recent studies reported better effectiveness of varenicline in women and in nicotine normal metabolizers phenotypically determined by nicotine-metabolite ratio. Our objective was to study the influence of nicotine-metabolite ratio, CYP2A6 genotype and sex on the response to nicotine replacement therapy and varenicline. Data were extracted from a longitudinal study which included smokers participating in a smoking cessation program. Response to treatment was defined by the absence of relapse when a set threshold of reduction in cigarettes per day relative to the week before the study was no more reached. The analysis considered total and partial reduction defined by a diminution of 100% and of 90% in cigarettes per day, respectively. The hazard ratio of relapsing was estimated in multivariate Cox regression models including the sex and the nicotine metabolism determined by the phenotype or by CYP2A6 genotyping (rs1801272 and rs28399433). In the normal metabolizers determined by phenotyping and in women, the hazard ratio for relapsing was significantly Public Significance StatementsThis study confirms that varenicline has better effectiveness than nicotine replacement therapy in nicotine normal metabolizers determined by the nicotine-metabolite ratio, and in women. The nicotine normal metabolizers determined by CYP2A6 rs1801272 genotyping also have greater response to varenicline than to nicotine replacement therapy. The choice of the smoking cessation pharmacological treatment should take into account nicotine metabolism and sex to obtain better abstinence rate in smokers.

The Use of the Nicotine Metabolite Ratio as a Biomarker to Personalize Smoking Cessation Treatment: Current Evidence and Future Directions

“…In a fifth study, the nonnicotine medication bupropion, which enhances dopaminergic neurotransmission, significantly enhanced quit rates for fast metabolizers of nicotine, but did not provide an added benefit for slow metabolizers (80). Similarly, Glatard and colleagues (81) showed, in a nonrandomized longitudinal study, that varenicline was a more effective treatment for smoking cessation than NRT for faster nicotine metabolizers. Varenicline, like bupropion, enhances dopaminergic neurotransmission by acting as a nicotinic partial agonist.…”

Evaluation of the nicotine metabolite ratio in smoking patients treated with varenicline and bupropion

“…This was the lowest success rate among slow metabolizers found in our analysis. Other studies have also shown a higher success rate among fast metabolizers when treated with varenicline, suggesting that nicotine replacement therapies are the most appropriate treatment for slow metabolizers (Glatard et al, 2017;Lerman et al, 2015). Shahab et al failed to demonstrate differences between varenicline and NRT therapy according to NRM in the realworld setting.…”

Genetic Variants in Smoking-Related Genes in Two Smoking Cessation Programs: A Cross-Sectional Study

“…This is probably due to miscegenation in the Mexican mestizo population in which the ancestral Amerindian component reaches 55% [ 22 ], and SNPs reported as CYP2A6 activity-related are mainly evaluated in Caucasian populations. We found differences among two cessation programs in two SNPs, rs28399433 and rs2431413; previously, the rs28399433 showed reduced apparent oral efavirenz clearance [ 23 ]; regarding nicotine metabolism, women and normal nicotine metabolizers (harboring the common allele) may benefit more from varenicline over nicotine replacement therapy [ 24 ]. Previously, our workgroup identified an association with a younger age at onset smoking [ 16 ], smoking status, age of onset, and psychological dependence in Mexican mestizo families [ 15 , 25 ].…”