Assessment of High Dose Transdermal Nicotine for Fast Metabolizers of Nicotine

Novel approaches to treating nicotine dependence remain a priority. The transdermal nicotine
patch is the most widely used form of tobacco dependence treatment, but only ~1 in 5 smokers
who use this treatment achieve cessation. One factor that may contribute to a poor response
to transdermal nicotine is inter-individual variability in the rate of nicotine metabolism,
which can be measured in saliva by the ratio of 3'hydroxycotinine (3-HC) to its precursor
cotinine.

Two clinical trials with transdermal nicotine have shown that the 3-HC/cotinine ratio
predicts response to transdermal nicotine such that faster metabolizers of nicotine (higher
3-HC/cotinine ratios) have lower quit rates, vs. slower nicotine metabolizers. Among
abstainers in these trials, the 3-HC/cotinine ratio also predicts therapeutic levels of
nicotine on transdermal nicotine, with faster metabolizers of nicotine exhibiting lower
nicotine. Thus, faster metabolizers of nicotine may require higher nicotine doses to achieve
the same therapeutic benefit from transdermal nicotine as do slow nicotine metabolizers.

To date, clinical trials have shown that, compared to the standard dose of transdermal
nicotine (21mg), higher doses (42mg) have no significant effect on quit rates. However, no
trial of high dose transdermal nicotine considered inter-individual variability in the rate
of nicotine metabolism. Thus, as a preliminary step toward conducting a fully-powered,
randomized clinical trial to assess standard vs. high dose transdermal nicotine for slow vs.
fast metabolizers of nicotine, we propose to evaluate, for the first time, the efficacy of
high-dose transdermal nicotine (vs. standard dose) among fast metabolizers of nicotine
(i.e., upper quartile of the 3-HC/cotinine ratio distribution).

We chose only fast metabolizers of nicotine for this trial since: 1) slow metabolizers of
nicotine exhibit high quit rates on standard transdermal nicotine and may experience adverse
effects from higher doses; and 2) as a "proof of concept" R21 application, our primary
objective is to test whether high doses of nicotine increase quit rates among fast
metabolizers of nicotine. Specifically, 100 smokers who are fast metabolizers of nicotine
will receive counseling and will be randomized to: 1) standard (1 X 21mg patch and 1 X
placebo patch), or 2) high dose (2 x 21mg patches) transdermal nicotine.

The primary outcome is biochemically-verified 7-day point prevalence cessation after 8 weeks
of treatment. Differences in patch-related side effects and mediators of transdermal
nicotine effects (e.g., nicotine levels, withdrawal) across the study conditions will also
be assessed.

Ultimately, this line of research hopes to provide the evidence necessary to translate
research on the 3-HC/cotinine ratio to clinical practice for the treatment of tobacco
dependence. Specifically, this research may show that a measure of nicotine metabolism rate
could be used to maximize the therapeutic benefits of transdermal nicotine by providing slow
metabolizers of nicotine with a standard patch dose and fast metabolizers of nicotine with
high dose transdermal nicotine. Identifying an effective treatment for faster metabolizers
of nicotine is also critical since these individuals are at increased risk for lung cancer.