Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial

Abstract

Summary Background There is substantial variability in therapeutic response and adverse effects with pharmacotherapies for tobacco dependence. Biomarkers to optimize treatment choice for individual smokers may improve treatment outcomes.Wetested whether a genetically-informed biomarker of nicotine clearance, the nicotine metabolite ratio (NMR; 3’hydroxycotinine/cotinine), predicts response to nicotine patch vs. varenicline for smoking cessation. Methods AnNMR-stratified multicenter, randomized, placebo-controlled clinical trial was conducted from November 2010-September 2013 at 4 sites. Treatment-seeking smokers (1246: 662 slow metabolizers; 584 normal metabolizers) were randomized to 11-weeks of nicotine patch (active patch + placebo pill), varenicline (active pill + placebo patch), or placebo (placebo pill + patch), plus behavioral counseling; an intent-to-treat analysis was conducted. Participants were followed for 12-months following the target quit date.The primary endpoint was biochemically verified 7-day point prevalence abstinence at the end of treatment (EOT) to estimate the pharmacologic effect of treatment by NMR. Secondary outcomes were side-effects, withdrawal symptoms, and 6- and 12-month abstinence rates. ClinicalTrials.govregistration: NCT01314001 Findings In the longitudinal model including all time points, the NMR-by-treatment interaction was significant (ratio of odds ratios (ORR)=1·96; CI=(1·11, 3·46); p=0·02). The results indicate that varenicline was more efficacious than nicotine patch for normal metabolizers, whilethe efficacy was equivalent for slow metabolizers. In cross-sectional analyses, the interaction was significant at EOT (ORR)=1·89; CI=(1·02, 3·45); p=0·04) andat 6-months (ORR=2·07; CI=(1·01, 4·22); p=0·05), but not at 12-months (p=0·14). An NMR-by-treatment interaction showed that slow (vs. normal) metabolizers reported greater overallside-effects severity with vareniclinevs. placebo (β−1·06; CI=(−2·08, −0·03); p=0·044). Interpretation Treating normal metabolizers with varenicline and slow metabolizers with nicotine patchmayoptimize quit rates while minimizing side-effects. Funding National Institutes of Health

Perceptions of Pharmacogenetic Research to Guide Tobacco Cessation by Patients, Providers and Leaders in a Tribal Healthcare Setting

“…These expectations may exceed the evidence supported by the present literature. It should be noted the use of pharmacogenetic testing as well as nicotine metabolic ratio has only just begun to predict successful smoking cessation in general [15][16][17][18]20,21], and has yet to be shown to do so in the AI/AN population specifically. However, the few concrete examples of pharmacogenetic testing altering clinical outcomes offer promise to cessation treatment adherence [16,17,42].…”

“…Use of pharmacogenetic testing to guide or personalize tobacco cessation therapy may improve patient outcomes [12][13][14][15][16][17][18]. Wide pharmacogenetic variation across racial and ethnic groups contributes to interindividual differences in drug metabolism, with implications for drug dosing, medication response and toxicity [19].…”

“…Wide pharmacogenetic variation across racial and ethnic groups contributes to interindividual differences in drug metabolism, with implications for drug dosing, medication response and toxicity [19]. Particular genetic variants of CYP2A6, CYP2B6, CHRNA5-A3-B4, CHRNB2, CHRNA5, CHRNA4 as well as nico tine metabolic ratio, a genetically informed biomarker, have been found to predict successful smoking cessation and response to pharmacotherapy (e.g., nicotine replacement therapy, varenicline, bupropion) [15][16][17][18]20,21]. AI/AN people have been historically underrepresented in medical research and may be less likely to benefit from current pharmacogenetic research and recommendations [19,[22][23][24].…”

Factors associated with the efficacy of smoking cessation treatments and predictors of smoking abstinence in EAGLES

“…In clinical practice in the United Kingdom, the relative efficacy of varenicline and NRT has been found to vary throughout different local services 24, but the service characteristics that underlie this are not known. Some evidence suggests that varenicline is more effective than NRT in smokers with ‘normal’ rates of nicotine metabolism, but not in those who metabolize nicotine slowly 25. However, the relative efficacy of different pharmacotherapies as a function of other phenotypes has not been studied.…”

Transdisciplinary translational behavioral (TDTB) research: opportunities, barriers, and innovations

“…Transdisciplinary research brings together perspectives from different disciplines, stakeholders, and/or levels of analysis to generate new breakthroughs-novel findings based on new conceptual models, methods, and approaches that may yield greater sustained effects over time. For instance, in a program of research spanning two decades, Lerman and colleagues have conducted innovative [7]. Furthermore, a series of discoveries by Lerman et al converged on the importance of working memory-related brain activity in smoking cessation, culminating in an fMRI-based predictive model of smoking relapse [8] and identification of a novel neuro-therapeutic target for behavior change interventions [9].…”