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Grant Details

Grant Number: 5U01DA020830-08 Interpret this number
Primary Investigator: Lerman, Caryn
Organization: University Of Pennsylvania
Project Title: Pharmacogenetics of Nicotine Addiction Treatment
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): 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. 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.

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Publications

Nicotine addiction.
Authors: Benowitz NL
Source: N Engl J Med, 2010 Jun 17;362(24), p. 2295-303.
PMID: 20554984
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New CYP2A6 gene deletion and conversion variants in a population of Black African descent.
Authors: Mwenifumbo JC, Zhou Q, Benowitz NL, Sellers EM, Tyndale RF
Source: Pharmacogenomics, 2010 Feb;11(2), p. 189-98.
PMID: 20136358
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Nicotinic acetylcholine receptor beta2 subunit (CHRNB2) gene and short-term ability to quit smoking in response to nicotine patch.
Authors: Perkins KA, Lerman C, Mercincavage M, Fonte CA, Briski JL
Source: Cancer Epidemiol Biomarkers Prev, 2009 Oct;18(10), p. 2608-12.
EPub date: 2009 Sep 15.
PMID: 19755656
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Genetic and environmental influences on the ratio of 3'hydroxycotinine to cotinine in plasma and urine.
Authors: Swan GE, Lessov-Schlaggar CN, Bergen AW, He Y, Tyndale RF, Benowitz NL
Source: Pharmacogenet Genomics, 2009 May;19(5), p. 388-98.
PMID: 19300303
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Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: a validation study.
Authors: Schnoll RA, Patterson F, Wileyto EP, Tyndale RF, Benowitz N, Lerman C
Source: Pharmacol Biochem Behav, 2009 Mar;92(1), p. 6-11.
EPub date: 2008 Oct 31.
PMID: 19000709
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Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics.
Authors: Benowitz NL
Source: Annu Rev Pharmacol Toxicol, 2009;49, p. 57-71.
PMID: 18834313
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Dopamine and opioid gene variants are associated with increased smoking reward and reinforcement owing to negative mood.
Authors: Perkins KA, Lerman C, Grottenthaler A, Ciccocioppo MM, Milanak M, Conklin CA, Bergen AW, Benowitz NL
Source: Behav Pharmacol, 2008 Sep;19(5-6), p. 641-9.
PMID: 18690118
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Gene and gene by sex associations with initial sensitivity to nicotine in nonsmokers.
Authors: Perkins KA, Lerman C, Coddington S, Jetton C, Karelitz JL, Wilson A, Jennings JR, Ferrell R, Bergen AW, Benowitz NL
Source: Behav Pharmacol, 2008 Sep;19(5-6), p. 630-40.
PMID: 18690117
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Gene-gene interactions between CYP2B6 and CYP2A6 in nicotine metabolism.
Authors: Ring HZ, Valdes AM, Nishita DM, Prasad S, Jacob P 3rd, Tyndale RF, Swan GE, Benowitz NL
Source: Pharmacogenet Genomics, 2007 Dec;17(12), p. 1007-15.
PMID: 18004205
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CYP2B6 genotype does not alter nicotine metabolism, plasma levels, or abstinence with nicotine replacement therapy.
Authors: Lee AM, Jepson C, Shields PG, Benowitz N, Lerman C, Tyndale RF
Source: Cancer Epidemiol Biomarkers Prev, 2007 Jun;16(6), p. 1312-4.
PMID: 17548706
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Identification of novel CYP2A6*1B variants: the CYP2A6*1B allele is associated with faster in vivo nicotine metabolism.
Authors: Mwenifumbo JC, Lessov-Schlaggar CN, Zhou Q, Krasnow RE, Swan GE, Benowitz NL, Tyndale RF
Source: Clin Pharmacol Ther, 2008 Jan;83(1), p. 115-21.
EPub date: 2007 May 23.
PMID: 17522595
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The pharmacogenetics research network: from SNP discovery to clinical drug response.
Authors: Giacomini KM, Brett CM, Altman RB, Benowitz NL, Dolan ME, Flockhart DA, Johnson JA, Hayes DF, Klein T, Krauss RM, Kroetz DL, McLeod HL, Nguyen AT, Ratain MJ, Relling MV, Reus V, Roden DM, Schaefer CA, Shuldiner AR, Skaar T, Tantisira K, Tyndale RF, Wang L, Weinshilboum RM, Weiss ST, Zineh I, Pharmacogenetics Research Network
Source: Clin Pharmacol Ther, 2007 Mar;81(3), p. 328-45.
PMID: 17339863
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Pharmacogenomics: challenges and opportunities.
Authors: Roden DM, Altman RB, Benowitz NL, Flockhart DA, Giacomini KM, Johnson JA, Krauss RM, McLeod HL, Ratain MJ, Relling MV, Ring HZ, Shuldiner AR, Weinshilboum RM, Weiss ST, Pharmacogenetics Research Network
Source: Ann Intern Med, 2006 Nov 21;145(10), p. 749-57.
PMID: 17116919
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CYP2A6 genotype and the metabolism and disposition kinetics of nicotine.
Authors: Benowitz NL, Swan GE, Jacob P 3rd, Lessov-Schlaggar CN, Tyndale RF
Source: Clin Pharmacol Ther, 2006 Nov;80(5), p. 457-67.
PMID: 17112802
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Human Variome Project: an international collaboration to catalogue human genetic variation.
Authors: Ring HZ, Kwok PY, Cotton RG
Source: Pharmacogenomics, 2006 Oct;7(7), p. 969-72.
PMID: 17054407
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