2010 — 2014 |
Lerman, Caryn [⬀] Tyndale, Rachel Fynvola |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Pharmacogenetics of Nicotine Addiction Treatment @ University of Pennsylvania
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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0.951 |
2010 — 2011 |
Tyndale, Rachel Fynvola |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
University of Toronto Coordinating Genetics Core &Clinical Trial Site @ University of Pennsylvania
Clinical Trials; Genetic; Nicotine Dependence; Pharmacogenetics; Site; Universities
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0.951 |
2012 — 2014 |
Tyndale, Rachel Fynvola |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
University of Toronto Coordinating Genetics Core & Clinical Trial Site @ University of Pennsylvania
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 foundafion of translafional pharmacogenefic (PGx) science conducted by this transdiscipiinary team during the past 4 vears. 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 underiying associations of our PGx marker with smoking cessation.
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0.951 |
2019 — 2021 |
Tyndale, Rachel Fynvola |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Variable Brain Oxycodone Metabolism Alters Drug Effect
7. Project Summary/Abstract Opioid drugs are effective pain-relievers that elicit analgesia through their action at brain µ-opioid receptors, simultaneously activating rewarding brain pathways, which can lead to opioid tolerance and drug dependence. The U.S. has the highest world-wide per capita use of opioids creating enormous health and societal costs related to addiction and treatment, lost productivity, and increased crime. Response to opioid drugs varies widely between people, and potentially between genders, but it is not clear why people experience different levels of pain relief from the same opioid, and why some people progress to become addicted. Many opioids are activated to even more potent µ-opioid receptor agonists by CYP2D enzymes, such as oxycodone that is converted to oxymorphone. However, oxymorphone is transported out of the brain and body more rapidly than oxycodone, hence oxycodone is responsible for analgesia. This project uses unique research methods to investigate how metabolism of opioids by CYP2D enzymes in the brain is important in oxycodone, tramadol and hydrocodone response. Both liver and brain CYP2D levels are regulated by genetics, but in addition, brain CYP2D is very sensitive to environmental chemicals, notably nicotine. Therefore, there can be two individuals who have the same CYP2D activity in the liver (same genetics) but very different levels of CYP2D activity in the brain, e.g. through smoking. Their drug and metabolite blood levels may be similar, but metabolism by brain CYP2D can alter oxycodone levels in the brain, influencing pain relief, tolerance and abuse liability. ?How does variation in oxycodone metabolism by CYP2D in the brain affect oxycodone analgesia and reward?? Validated rat models of analgesia, tolerance and reward, will be used with drug and dopamine microdialysis, pharmacokinetic modelling, and established methods of manipulating brain but not liver CYP2D levels. Brain CYP2D will be reduced by injecting chemical inhibitors into the brain, and increased by chronic systemic nicotine treatment. Decreased brain CYP2D should increase analgesia, tolerance and reward through reduced oxycodone conversion to oxymorphone, resulting in higher brain oxycodone levels. Increased brain CYP2D should decrease analgesia, tolerance and reward through greater metabolism of oxycodone to oxymorphone, resulting in lower brain oxycodone levels. Plasma oxycodone and metabolites levels will not change as liver CYP2D is unaffected by these manipulations. Two additional CYP2D substrates, the commonly prescribed oral opioids, hydrocodone and tramadol, and sex differences in oxycodone responses will also be investigated. This will improve mechanistic understanding of this novel source of variation between people in their opioid response, and identification of individuals at risk for opioid pain-treatment failure and progression to dependence on these widely used oral opioids. Extensive PB-PK modelling will assist in extrapolations to human, as will planned human PET imaging studies. The knowledge acquired from this project will contribute to our on-going efforts to reduce the societal and health costs of opioid drug misuse and dependence.
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