Pharmacogenetics of Nicotine Addiction Treatment

Conditions

Nicotine Addiction

Keywords

Tobacco, Smoking, Varenicline, Nicotine Patch

Brief summary

The purpose of this research program is to understand how a biomarker called the nicotine metabolite ratio (also referred to as NMR) may influence a smoker's ability to quit smoking.

Detailed description

Smoking is an enormous public health problem with a great need for research to improve treatment outcomes. Our prior data indicates that the cytochrome P450 2A6 (CYP2A6) enzyme is critical in the metabolic inactivation of nicotine, and also influences smoking behavior and response to therapies. 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 CYP2A6 genetic variation and environmental influences on CYP2A6 activity. The NMR is measured non-invasively in smokers with established reliability, stability, analytic validity, and efficacy as a predictor of the ability to quit smoking and treatment response in multiple retrospective trials. Translation of these findings to clinical practice requires validation in a prospective clinical trial comparing alternative therapies for smoking cessation. Thus, the proposed trial is a prospective, stratified, placebo-controlled, multi-center clinical trial of alternative therapies for smoking cessation treatment in approximately 1,200 smokers. Randomization to placebo (PLA), transdermal nicotine (TN), or varenicline (VAR) will be stratified prospectively based on the nicotine metabolite ratio (NMR). Abstinence from smoking at the end of treatment will be the primary outcome. Quit rate at 6-month follow-up is a secondary outcome. To facilitate translation to practice, analysis of the cost-effectiveness of our proposed approach will also be completed. 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.

Tonkin SS, Betts JM, Dowd AN, Mahoney MC, Cinciripini PM, Schnoll RA, George TP, Tyndale RF, Hawk LW.

2025-11-01

10.1093/ntr/ntaf095

Sex dependent genetic architecture of biochemically verified tobacco use.

Chenoweth MJ, Lerman C, Knight J, Tyndale RF.

2025-03-26

10.1016/j.psychres.2025.116465

Genetic Prediction of Smoking Cessation Medication Side Effects: A Genome‐Wide Investigation of Abnormal Dreams on Varenicline

Meghan J. Chenoweth, Yong‐Jae Kim, Nicole L. Nollen, Larry W. Hawk, Martin C. Mahoney et al. (8 authors)

Clinical Pharmacology & Therapeutics2024-02-191 citations

10.1002/cpt.3210

Influence of <i>CYP2A6</i> Genetic Variation, Nicotine Dependence Severity, and Treatment on Smoking Cessation Success

Meghan J. Chenoweth, Caryn Lerman, Jo Knight, Rachel F. Tyndale

Nicotine & Tobacco Research2023-02-158 citations

10.1093/ntr/ntac268

Evaluating Treatment Mechanisms of Varenicline: Mediation by Affect and Craving

Sarah Tonkin, Craig R. Colder, Martin C. Mahoney, Gary E. Swan, Paul M. Cinciripini et al. (9 authors)

Nicotine & Tobacco Research2022-05-267 citations

10.1093/ntr/ntac138

Analyses of nicotine metabolism biomarker genetics stratified by sex in African and European Americans

Meghan J. Chenoweth, Lisa Sanderson Cox, Nicole L. Nollen, Jasjit S. Ahluwalia, Neal L. Benowitz et al. (8 authors)

Scientific Reports2021-10-0117 citations

10.1038/s41598-021-98883-z

A Genome-Wide Association Study of Nausea Incidence in Varenicline-Treated Cigarette Smokers

Meghan J. Chenoweth, Caryn Lerman, Jo Knight, Rachel F. Tyndale

Nicotine & Tobacco Research2021-03-115 citations

10.1093/ntr/ntab044

Impact of early nausea on varenicline adherence and smoking cessation

Annie R. Peng, Walter Swardfager, Neal L. Benowitz, Jasjit S. Ahluwalia, Caryn Lerman et al. (7 authors)

Addiction2019-09-1027 citations

10.1111/add.14810

Differences in the rate of nicotine metabolism among smokers with and without HIV.

Ashare RL, Thompson M, Leone F, Metzger D, Gross R, Mounzer K, Tyndale RF, Lerman C, Mahoney MC, Cinciripini P, George TP, Collman RG, Schnoll R.

2019-05-0146 citations

10.1097/qad.0000000000002127

Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity

Ahmed El‐Boraie, Taraneh Taghavi, Meghan J. Chenoweth, Koya Fukunaga, Taisei Mushiroda et al. (10 authors)

Addiction Biology2019-02-2731 citations

10.1111/adb.12741

Predicting smoking abstinence with biological and self-report measures of adherence to varenicline: Impact on pharmacogenetic trial outcomes.

Peng AR, Schnoll R, Hawk LW, Cinciripini P, George TP, Lerman C, Tyndale RF.

2018-06-2611 citations

10.1016/j.drugalcdep.2018.04.035

Genome-wide association study of a nicotine metabolism biomarker in African American smokers: impact of chromosome 19 genetic influences.

Chenoweth MJ, Ware JJ, Zhu AZX, Cole CB, Cox LS, Nollen N, Ahluwalia JS, Benowitz NL, Schnoll RA, Hawk LW, Cinciripini PM, George TP, Lerman C, Knight J, Tyndale RF, PGRN-PNAT Research Group.

2017-11-0244 citations

10.1111/add.14032

The Nicotine Metabolite Ratio is Associated With Early Smoking Abstinence Even After Controlling for Factors That Influence the Nicotine Metabolite Ratio.

Chenoweth MJ, Schnoll RA, Novalen M, Hawk LW, George TP, Cinciripini PM, Lerman C, Tyndale RF.

2015-06-1121 citations

10.1093/ntr/ntv125

Test-Retest Reliability and Stability of the Nicotine Metabolite Ratio Among Treatment-Seeking Smokers

Diana A. Hamilton, Martin C. Mahoney, Maria Novalen, Meghan J. Chenoweth, Daniel F. Heitjan et al. (8 authors)

Nicotine & Tobacco Research2015-03-0117 citations

10.1093/ntr/ntv031

Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial.

Lerman C, Schnoll RA, Hawk LW, Cinciripini P, George TP, Wileyto EP, Swan GE, Benowitz NL, Heitjan DF, Tyndale RF, PGRN-PNAT Research Group.

2015-01-12245 citations

10.1016/s2213-2600(14)70294-2

Known and novel sources of variability in the nicotine metabolite ratio in a large sample of treatment-seeking smokers.

Chenoweth MJ, Novalen M, Hawk LW, Schnoll RA, George TP, Cinciripini PM, Lerman C, Tyndale RF.

2014-07-1094 citations

10.1158/1055-9965.epi-14-0427

Interventions

DRUGVarenicline

Day 1-3: 0.5mg once daily orally Day 4-7: 0.5mg twice daily orally Day 8-84: 1.0mg twice daily orally

DRUGPlacebo

Day 1-3: 0.5mg once daily orally Day 4-7: 0.5mg twice daily orally Day 8-84: 1.0mg twice daily orally Week 1 - 6: 21mg placebo patch Week 7 - 8: 14mg placebo patch Week 9 - 11: 7mg placebo patch

DRUGTransdermal Nicotine

Week 1-6: 21mg nicotine patch Week 7-8: 14mg nicotine patch Week 9-11: 7mg nicotine patch

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

No

Inclusion criteria

Eligible participants will be males and females 1. Between the ages of 18-65. 2. Smoke at least 10 cigarettes/day for the past 6 months. 3. Provide a baseline Carbon Monoxide (CO) reading greater than 10ppm at the Intake Session. 4. Are seeking smoking cessation treatment. 5. Plan to live in the area for the next 12 months. 6. Fluent English speaker. 7. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and Health Insurance Portability and Accountability Act (HIPAA) form. All subjects must consent to use a medically accepted method of birth control (e.g., condoms and spermicide, oral contraceptive, Depo-Provera injection, contraceptive patch, tubal ligation) or abstain from sexual intercourse during the time they are taking study medication (pills and patches) and for at least one month after the medication period ends. All female subjects of child-bearing potential should not be pregnant for the duration of the study.

Exclusion criteria

Smoking Behavior 1. Regular (daily) use of chewing tobacco, snuff or snus. 2. Current enrollment or plans to enroll in another smoking cessation or research program in the next 12 months. 3. Plan to use other nicotine substitutes or smoking cessation treatments in the next 12 months. 4. Provide a baseline CO reading less than or equal to 10ppm at the Intake Session. Alcohol/Drug

Design outcomes

Primary

Measure	Time frame	Description
7-day Point Prevalence Quit Rate at End-of-Treatment (EOT)	Week 11	The percentage of ITT subjects who were verified as abstinent. Abstinence was defined as no self-reported smoking (not even a puff) for at least 7 days before the telephone assessment, with in-person verification for those self-reporting abstinence. In-person verification consisted of breath carbon monoxide analysis, with a reading of 8 parts-per-million or less confirming abstinence. Subjects who were lost to follow-up were considered smokers.

Secondary

Measure	Time frame	Description
7-day Point Prevalence Quit Rate at 6-month Follow up Survey	Week 24	The percentage of ITT subjects who were verified as abstinent at the 6-month follow up survey. Abstinence was defined as no self-reported smoking (not even a puff) for at least 7 days before the telephone assessment, with in-person verification for those self-reporting abstinence. In-person verification consisted of breath carbon monoxide analysis, with a reading of 8 parts-per-million or less confirming abstinence. Subjects who were lost to follow-up were considered smokers.
Total Side-Effect Severity Index at Pre-Quit	Pre-Quit (Week -1/Baseline)	The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers). Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects.
Total Side-Effect Severity Index at Target Quit Date	Target Quit Date (Week 0)	The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers). Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects.
Total Side-Effect Severity Index at Week 1	Week 1	The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers). Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects.
Total Side-Effect Severity Index at Week 4	Week 4	The mean side-effect severity score by treatment group (placebo vs. nicotine patch vs. varenicline) and by NMR group (slow metabolizers vs. normal metabolizers). Side-effect severity was calculated using a Side Effects Checklists (SEC). 29 common side-effects associated with transdermal nicotine or varenicline treatment were rated by participants on a 0 (none) to 3 (severe) scale. For each participant at this timepoint, these scores were summed to calculate a total score, with a range of 0 to 87; a higher score indicated a higher severity of side-effects.

Countries

Canada, United States

Participant flow

Recruitment details

The trial was conducted at four academic medical centers. From 11/16/2010 to 9/16/2013, participants were recruited through advertisements for a free smoking cessation program.

Pre-assignment details

Subjects were randomly assigned to one of three treatment groups in a 1:1:1 ratio: Placebo; Nicotine Patch; or Varenicline. Randomization was stratified by nicotine metabolite ratio - slow metabolizers of nicotine vs. normal metabolizers - and study site and blocked in blocks of 12 to maintain balance. Slow metabolizers were over-sampled.

Participants by arm

Arm	Count
Placebo (Slow Metabolizers) Slow metabolizers * Taking placebo pills daily for 12 weeks * Wearing placebo patches daily for 11 weeks * Received smoking cessation counseling during their sessions	215
Placebo (Normal Metabolizers) Normal metabolizers * Taking placebo pills daily for 12 weeks * Wearing placebo patches daily for 11 weeks * Received smoking cessation counseling during their sessions	193
Nicotine Patch (Slow Metabolizers) Slow metabolizers * Taking placebo pills daily for 12 weeks * Wearing active nicotine patches for 11 weeks (6 weeks of 21mg, 2 weeks of 14mg, 3 weeks of 7mg) * Received smoking cessation counseling during their sessions	227
Nicotine Patch (Normal Metabolizers) Normal metabolizers * Taking placebo pills daily for 12 weeks * Wearing active nicotine patches for 11 weeks (6 weeks of 21mg, 2 weeks of 14mg, 3 weeks of 7mg) * Received smoking cessation counseling during their sessions	191
Varenicline (Slow Metabolizers) Slow metabolizers * Taking active varenicline pills daily for 12 weeks (3 days of 0.5mg daily, 4 days of 0.5mg twice daily, and 77 days of 1mg twice daily) * Wearing placebo patches for 11 weeks * Received smoking cessation counseling during their sessions	220
Varenicline (Normal Metabolizers) Normal metabolizers * Taking active varenicline pills daily for 12 weeks (3 days of 0.5mg daily, 4 days of 0.5mg twice daily, and 77 days of 1mg twice daily) * Wearing placebo patches for 11 weeks * Received smoking cessation counseling during their sessions	200
Total	1,246

Baseline characteristics

Characteristic	Varenicline (Normal Metabolizers)	Total	Placebo (Slow Metabolizers)	Placebo (Normal Metabolizers)	Nicotine Patch (Slow Metabolizers)	Nicotine Patch (Normal Metabolizers)	Varenicline (Slow Metabolizers)
Age, Continuous	46 years STANDARD_DEVIATION 12	45 years STANDARD_DEVIATION 11	44 years STANDARD_DEVIATION 11	47 years STANDARD_DEVIATION 11	46 years STANDARD_DEVIATION 11	46 years STANDARD_DEVIATION 11	44 years STANDARD_DEVIATION 12
Annual Income (US dollars) Greater than or equal to US$50,000	71 participants	446 participants	65 participants	79 participants	82 participants	75 participants	74 participants
Annual Income (US dollars) Less than US$50,000	129 participants	800 participants	150 participants	114 participants	145 participants	116 participants	146 participants
Cigarettes per day	18.4 cigarettes per day STANDARD_DEVIATION 6.3	18.0 cigarettes per day STANDARD_DEVIATION 7	17.6 cigarettes per day STANDARD_DEVIATION 7	19.6 cigarettes per day STANDARD_DEVIATION 8.7	17.6 cigarettes per day STANDARD_DEVIATION 7	18.5 cigarettes per day STANDARD_DEVIATION 7	16.7 cigarettes per day STANDARD_DEVIATION 5.4
Education level High school education or lower	61 participants	387 participants	68 participants	57 participants	78 participants	49 participants	74 participants
Education level Post-high school education	139 participants	859 participants	147 participants	136 participants	149 participants	142 participants	146 participants
Employment Status Employed	125 participants	780 participants	136 participants	109 participants	158 participants	120 participants	132 participants
Employment Status Not employed	75 participants	466 participants	79 participants	84 participants	69 participants	71 participants	88 participants
FTND Score	2.1 units on a scale STANDARD_DEVIATION 2.02	5.2 units on a scale STANDARD_DEVIATION 1.97	5.3 units on a scale STANDARD_DEVIATION 1.92	5.4 units on a scale STANDARD_DEVIATION 2	5.2 units on a scale STANDARD_DEVIATION 2	5.3 units on a scale STANDARD_DEVIATION 1.89	5.1 units on a scale STANDARD_DEVIATION 2
Race/Ethnicity, Customized Black	53 participants	462 participants	95 participants	56 participants	94 participants	57 participants	107 participants
Race/Ethnicity, Customized Other	14 participants	91 participants	23 participants	9 participants	16 participants	15 participants	14 participants
Race/Ethnicity, Customized White	133 participants	693 participants	97 participants	128 participants	117 participants	119 participants	99 participants
Region of Enrollment Canada	44 participants	276 participants	47 participants	43 participants	52 participants	42 participants	48 participants
Region of Enrollment United States	156 participants	970 participants	168 participants	150 participants	175 participants	149 participants	172 participants
Sex: Female, Male Female	99 Participants	543 Participants	83 Participants	91 Participants	88 Participants	94 Participants	88 Participants
Sex: Female, Male Male	101 Participants	703 Participants	132 Participants	102 Participants	139 Participants	97 Participants	132 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	194 / 215	171 / 193	206 / 227	169 / 191	210 / 220	185 / 200
serious Total, serious adverse events	10 / 215	6 / 193	11 / 227	11 / 191	3 / 220	8 / 200

Outcome results

Primary

7-day Point Prevalence Quit Rate at End-of-Treatment (EOT)

The percentage of ITT subjects who were verified as abstinent. Abstinence was defined as no self-reported smoking (not even a puff) for at least 7 days before the telephone assessment, with in-person verification for those self-reporting abstinence. In-person verification consisted of breath carbon monoxide analysis, with a reading of 8 parts-per-million or less confirming abstinence. Subjects who were lost to follow-up were considered smokers.

Time frame: Week 11