PNAT Profile
Pharmacogenetics of Nicotine Addiction Treatment
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Abstract (Updated, November 2011)
Smoking is an enormous public health 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 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 mediates the metabolic inactivation of nicotine to cotinine (and the further metabolism to 3hydroxycotinine) which is highly correlated with nicotine clearance. We have also shown that inherited variation in nicotine clearance influences quitting smoking and in response to cessation medications. 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 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 this approach using both primary data and simulation models. In addition to these goals, we propose within this U01 to identify additional sources of genetic variation in nicotine clearance and the NMR, and to determine NMR in multiple biospecimens in order to facilitate use in clinical practice. We will also investigate additional pharmacokinetic and pharmacodynamic gene associations with therapeutic response. 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. 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 treatment is a major public health priority.
PNAT Team
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Lerman, Caryn, Ph.D. Principal Investigator, Head Clinical Core Email: clerman@mail.med.upenn.edu Phone: (215) 746-7151 |
Tyndale, Rachel, Ph. D. Principal Investigator, Head Genetics Core Email: r.tyndale@utoronto.ca Phone: (416) 978-6374 |
Baldwin, Donald, Dr. Co-Investigator Email: dbaldwin@mail.med.upenn.edu Phone: (215) 898-3675 |
Benowitz, Neal, Dr. Co-Investigator Email: nbenowitz@medsfgh.ucsf.edu Phone: (415) 206-8324 |
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Bergen, Andrew, Dr. Co-Investigator Email: andrew.bergen@sri.com Phone: (650) 859-4618 |
Cinciripini, Paul, Dr. Co-Investigator, Clinical Site PI Email: pcinciri@mdanderson.org Phone: (713) 745-1868 |
Conti, David, Dr. Co-Investigator Email: dconti@usc.edu Phone: (323) 442-3140 |
George, Tony, Dr. Co-Investigator, Clinical Site PI Email: tony_george@camh.net Phone: (416) 535-8501, ext. 4544 |
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Glick, Henry, Dr. Co-Investigator, Health Economics Email: glickh@mail.med.upenn.edu Phone: (215) 898-6868 |
Hawk, Larry, Dr. Co-Investigator, Clinical Site PI Email: lhawk@buffalo.edu Phone: (716) 645-0192 |
Heitjan, Daniel, Dr. Head, Biostatistics Core Email: dheitjan@mail.med.upenn.edu Phone: (215) 573-7328 |
Landis, Richard, Dr. Co-Investigator Email: jrlandis@mail.med.upenn.edu Phone: (215) 573-4922 |
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Leone, Frank, Dr. Co-Investigator Email: frank.tleone@uphs.upenn.edu Phone: (215) 662-8585 |
Polsky, Daniel, Dr. Co-Investigator, Health Economics Email: polsky@mail.med.upenn.edu Phone: (215) 573-5752 |
Schnoll, Robert, Dr. Co-Investigator, Clinical Site PI Email: schnoll@mail.med.upenn.edu Phone: (215) 746-7143 |
Selby, Peter, Dr. Co-Investigator, Clinical Site PI Email: peter_selby@camh.net Phone: (416) 535-8501 ext. 6859 |
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Swan, Gary, Dr. Co-Investigator Email: gary.swan@sri.com Phone: (650) 859-5322 |