Program Goals and Scope. Tobacco use is the foremost cause of premature death in the U.S. About 21% of adults are current smokers and smoking rates have not declined in recent years. Although available pharmacotherapies can aid in quitting smoking, quit rates vary substantially in subgroups of smokers. Thus, smoking is a significant clinical problem with a great need for research to improve treatment outcomes. The goal of the Pharmacogenetics of Nicotine Addiction Treatment (PNAT) research program is to generate the evidence base to optimize pharmacotherapeutic choices for individuals who wish to quit smoking. Building upon a strong foundation of translational pharmacogenetic (PGx) science conducted by this transdisciplinary team during the past 4 years. we propose in this competing renewal to: (a) conduct a multi-center prospective stratified PGx clinical trial to establish the predictive validity and cost-effectiveness of a genetically-informed biomarker to optimize smoking cessation treatment;(b) identify additional gene variants altering nicotine pharmacokinetics (PK), as well as pharmacodynamic (PD) gene variants influencing therapeutic response;and (c) elucidate causal mechanisms underlying associations of our PGx marker with smoking cessation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DA020830-09
Application #
8505444
Study Section
Special Emphasis Panel (ZRG1-GGG-M)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$240,110
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Chenoweth, Meghan J; Zhu, Andy Z X; Sanderson Cox, Lisa et al. (2014) Variation in P450 oxidoreductase (POR) A503V and flavin-containing monooxygenase (FMO)-3 E158K is associated with minor alterations in nicotine metabolism, but does not alter cigarette consumption. Pharmacogenet Genomics 24:172-6
Zhu, Andy Z X; Zhou, Qian; Cox, Lisa Sanderson et al. (2014) Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes. Drug Metab Dispos 42:1971-7
Cascorbi, I; Tyndale, R (2014) Progress in pharmacogenomics: bridging the gap from research to practice. Clin Pharmacol Ther 95:231-5

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