The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

SummaryWhile several lung cancer susceptibility loci have been identified, much of lung cancer heritability remains unexplained. Here, 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

The 3HC/COT ratio derived from nicotine either administered as a probe drug or from tobacco use, measured in either plasma or saliva, is highly correlated with the oral clearance of nicotine. The ratio appears to be a useful noninvasive marker of the rate of nicotine metabolism (which is important in studying nicotine addiction and smoking behavior), as well as a general marker of CYP2A6 activity (which is important in studying drug and toxin metabolism).

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

Genetically variable CYP2A6 is the primary enzyme that inactivates nicotine to cotinine. Our objective was to investigate allele frequencies among five ethnic groups and to investigate the relationship between genetically slow nicotine metabolic inactivation and smoking status, cigarette consumption, age of first smoking and duration of smoking. Chinese, Japanese, Canadian Native Indian, African-North American and Caucasian DNA samples were assessed for CYP2A6 allelic frequencies (CYP2A6*1B-*12,*1x2). Adult Caucasian non-smokers (n = 224) (1-99 cigarettes/lifetime) and smokers (n = 375) (> or = 100 cigarettes/lifetime) were assessed for demographics, tobacco/drug use history and DSM-IV dependence and genotyped for CYP2A6 alleles associated with decreased nicotine metabolism (CYP2A6*2, CYP2A6*4, CYP2A6*9, CYP2A6*12). CYP2A6 allele frequencies varied substantially among the ethnic groups. The proportion of Caucasian slow nicotine inactivators was significantly lower in current, DSM-IV dependent smokers compared to non-smokers [7.0% and 12.5%, respectively, P = 0.03, odds ratio (OR) = 0.52; 95% confidence interval (CI) 0.29-0.95]; non-dependent smokers showed similar results. Daily cigarette consumption (cigarettes/day) was significantly (P = 0.003) lower for slow (21.3; 95% CI 17.4-25.2) compared to normal inactivators (28.2; 95% CI 26.4-29.9); this was observed only in DSM-IV dependent smokers. Slow inactivators had a significantly (P = 0.03) lower age of first smoking compared to normal inactivators (13.0 years of age; 95% CI 12.1-14.0 versus 14.2; 95% CI 13.8-14.6), and a trend towards smoking for a shorter duration. This study demonstrates that slow nicotine inactivators are less likely to be adult smokers (dependent or non-dependent). Slow inactivators also smoked fewer cigarettes per day and had an earlier age of first smoking (only dependent smokers).

The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine’s Standards for Developing Trustworthy Clinical Practice Guidelines.

The nicotine metabolite ratio might be useful in screening smokers to determine likely success with a standard dose of transdermal nicotine.

CYP2A6 is the main nicotine metabolizing enzyme in humans. We investigated the relationships between CYP2A6 genotype, baseline plasma 3HC/COT (a phenotypic marker of CYP2A6 activity), and smoking behaviors in African-American light smokers. Cigarette consumption, age of initiation, and dependence scores did not differ between 3HC/COT quartiles or CYP2A6 genotype groups. Slow metabolizers (both genetic and phenotypic) had significantly higher plasma nicotine levels suggesting cigarette consumption was not reduced to adjust for slower rates of nicotine metabolism. Individuals in the slowest 3HC/COT quartile had higher quit rates with both placebo and nicotine gum treatments (OR 1.85, 95% CI 1.08-3.16, p = 0.03). Similarly, the slowest CYP2A6 genotype group had higher quit rates, although this did not reach significance (OR 1.61, 95% CI 0.95-2.72, p = 0.08). 3HC/COT ratio, and possibly CYP2A6 genotype, may be useful in the future for personalizing the choice of smoking cessation treatment for African-American light smokers.