Smoking is a significant public health problem, and there is a great need for research to improve smoking cessation treatment outcomes. The goal of the Pharmacogenetics of Nicotine Addiction Treatment (PNAT) research program is to generate the evidence base to optimize treatment decisions for Individuals who want to quit smoking. During the past 4 years of PNAT1, we have characterized genetic variants altering nicotine pharmacokinetics as well as pharmacodynamic genetic variants influencing response to pharmacotherapies for smoking cessation treatment. We have shown that the CYP2A6 enzyme is critical in the metabolic inactivation of nicotine, and inherited variation in nicotine clearance influences smoking behavior and cessation. With a vision toward translation of our research to practice, we have characterized a genetically-informed biomarker of CYP2A6 activity, specifically the nicotine metabolite ratio (NMR;3'hydroxycotinine/cotinine), which reflects both genetic and environmental influences on CYP2A6 activity and nicotine clearance. The NMR is measured noninvasively in smokers with established reliability, stability, analytic validity, and efficacy as a predictor of therapeutic response in multiple independent (retrospective) clinical trials. Translation of these findings to clinical practice, the ultimate goal of the PGRN, requires validation In a prospective stratified clinical trial comparing alternative therapies for smoking cessation. In this competing renewal, we propose to conduct a prospective placebo-controlled multi-center pharmacogenetic (PGx) clinical trial of alternative therapies for smoking cessation treatment in 1,350 smokers. Randomization to placebo, transdermal nicotine, or varenicline will be stratified prospectively based on the NMR, the most robust genetically-informed biomarker for smoking cessation identified to date. Further, to facilitate translation to practice, we will determine the cost-effectiveness of our proposed PGx approach using both primary data and simulation models. In addition to these goals, we propose within this UOI to: identify additional sources of genetic variation in nicotine clearance and the NMR;investigate additional pharmacokinetic and pharmacodynamic gene associations with therapeutic response biomarker;and elucidate the mechanisms involved in identified PGx effects on smoking cessation. The proposed research provides the next critical step to validate a genetically-informed diagnostic tool, the NMR, which clinicians can use in the future to optimize treatment decisions for their patients who wish to quit smoking. As outlined recently by NIDA, due to the devastating health consequences of smoking and the urgent demand for better treatments, the validation of biomarker strategies to improve the outcomes of treatments a major public health priority.

Public Health Relevance

The ultimate goal of this research is to validate a genetically-informed diagnostic tool which clinicians can use in the future to optimize treatment decisions for their patients who smoke. Due to the enormous adverse impact of tobacco use, this research has high public health significance.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DA020830-07
Application #
8119699
Study Section
Special Emphasis Panel (ZRG1-GGG-M (52))
Program Officer
Bough, Kristopher J
Project Start
2005-09-15
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
7
Fiscal Year
2011
Total Cost
$2,705,047
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chenoweth, Meghan J; Tyndale, Rachel F (2017) Pharmacogenetic Optimization of Smoking Cessation Treatment. Trends Pharmacol Sci 38:55-66
Ware, Jennifer J; Tanner, Julie-Anne; Taylor, Amy E et al. (2017) Does coffee consumption impact on heaviness of smoking? Addiction 112:1842-1853
Ashare, Rebecca L; Lerman, Caryn; Tyndale, Rachel F et al. (2017) Sleep Disturbance During Smoking Cessation: Withdrawal or Side Effect of Treatment? J Smok Cessat 12:63-70
Tanner, Julie-Anne; Prasad, Bhagwat; Claw, Katrina G et al. (2017) Predictors of Variation in CYP2A6 mRNA, Protein, and Enzyme Activity in a Human Liver Bank: Influence of Genetic and Nongenetic Factors. J Pharmacol Exp Ther 360:129-139
Peng, Annie R; Morales, Mark; Wileyto, E Paul et al. (2017) Measures and predictors of varenicline adherence in the treatment of nicotine dependence. Addict Behav 75:122-129
Chenoweth, Meghan J; Ware, Jennifer J; Zhu, Andy Z X et al. (2017) Genome-wide association study of a nicotine metabolism biomarker in African American smokers: impact of chromosome 19 genetic influences. Addiction :
Tanner, Julie-Anne; Henderson, Jeffrey A; Buchwald, Dedra et al. (2017) Variation in CYP2A6 and nicotine metabolism among two American Indian tribal groups differing in smoking patterns and risk for tobacco-related cancer. Pharmacogenet Genomics 27:169-178
Schuit, Ewoud; Panagiotou, Orestis A; Munafò, Marcus R et al. (2017) Pharmacotherapy for smoking cessation: effects by subgroup defined by genetically informed biomarkers. Cochrane Database Syst Rev 9:CD011823
Taghavi, Taraneh; St Helen, Gideon; Benowitz, Neal L et al. (2017) Effect of UGT2B10, UGT2B17, FMO3, and OCT2 genetic variation on nicotine and cotinine pharmacokinetics and smoking in African Americans. Pharmacogenet Genomics 27:143-154
Li, Sufang; Yang, Yihong; Hoffmann, Ewa et al. (2017) CYP2A6 Genetic Variation Alters Striatal-Cingulate Circuits, Network Hubs, and Executive Processing in Smokers. Biol Psychiatry 81:554-563

Showing the most recent 10 out of 160 publications