Pharmacokinetics of Nicotine Film in Smokers

Briefly, this will be a two-part pharmacokinetic study, each part involving 12 participants.

In Part 1, 4 volunteer smokers (both male, and female) each will each abstain from all
tobacco/nicotine products for 16 hours before attending the Penn State Clinical Research
Center for the measurement of the blood nicotine pharmacokinetic response to a randomly
allocated dose of either (a) 0mg, (b) 2mg or (c) 4mg oral nicotine film. A trained nurse will
implant an intravenous indwelling catheter in each participant, through which they will
provide a baseline blood sample after 16 hours of abstinence, confirmed by an exhaled
carbon-monoxide < 6 ppm, and then will place a nicotine film in their mouth and have blood
drawn every 10 minutes for the next 60 minutes, and then every 30 minutes for the next 2
hours plus one blood draw one minute after the film dissolves (11 blood draws in all over 3
hours after using the nicotine film). Subjective measures of (a) nicotine withdrawal and
craving and (b) potential nicotine effects, including symptoms of nicotine intoxication, will
be recorded at scheduled intervals through the study visit, and blood pressure and heart rate
will be measured every 30 minutes. The investigators expect to find peak blood nicotine
concentrations of around 3-4 ng/ml and 5-6 ng/ml from each of the two active doses of
nicotine film, with the peak occurring approximately 30 minutes after film administration,
and the level having dropped by at least half by 2 hours later. These peak blood nicotine
levels are all within the range that a smoker might obtain after smoking a single cigarette.
Upon completion of all blood draws, a trained nurse will remove the catheter and treat the
puncture wound. The participant will receive $120 for this visit.

In Part 2, 12 participants will again attend the Penn State Clinical Research Center after 16
hours of abstinence, confirmed by an exhaled carbon monoxide < 12 ppm. On this visit
participants will consume repeated doses of nicotine films intended to mimic the patterns of
delivery that will be used in smoking cessation study 2 and fMRI study 3. The primary issue
here is to determine peak blood nicotine concentrations and safety resulting from (a) the
highest dose schedule that could be used in study 2 and 3, (b) the steady state levels
produced by repeated administration of the 2mg nicotine film, and (c) to compare the
subjective effects to placebo. In order to mimic the most aggressive dosing schedule possible
in the "random nicotine" arm of study 2 and 3, the investigators will assess blood nicotine,
subjective and basic cardiovascular responses to consuming nicotine film every 3 hours
beginning at 8:00 a.m. on the following schedule: 4mg, 4mg, 0mg, 4mg.

All 12 participants will attend after 16 hours nicotine abstinence. 4 subjects each will be
randomly allocated to consume 4 films over 12 hours in each of the following orders (a)
0,0,0,0 mg (b) 2,2,2,2 or (c) 4,4,0,4. A blood sample will be drawn at baseline prior to each
film administration, and then at 30, 60 and 120 minutes after each film administration as
well as one minute after film dissolution (20 blood draws in total), with heart rate and BP
being assessed every 30 minutes. Nicotine has a half-life of approximately 2 hours, so the
investigators expect that with 3-hourly administration there will not be much build-up of
nicotine levels and these levels will be on the low end of the typical levels experienced by
smokers every day. The participants will each receive $240 for this visit.

At clinic visits, in addition to providing blood samples for measurement of plasma nicotine
concentration, participants will be asked to complete a battery of survey instruments
assessing subjective effects (e.g. withdrawal and craving) and physical symptoms (e.g.
dizziness and nausea) that could be caused by either nicotine withdrawal or nicotine
exposure.

Inclusion Criteria:

1. Aged 18 - 55

2. Smoke >9 cigarettes/day for at least the past 12 months

3. Able to understand and consent to study procedures

4. Able to read and write in English

5. Exhaled Carbon Monoxide <12 ppm at in-person screening

Exclusion Criteria:

1. Unstable or significant medical conditions and conditions such as elevated blood
pressure (Systolic >140 mm Hg or diastolic >90mm Hg at baseline), COPD and those that
are likely to affect biomarker data such as kidney or liver disease.

2. Individuals with sodium-restricted diet, heart disease, recent heart attack, irregular
heartbeat, stomach ulcers, or diabetes as well as those taking prescription
medications for depression or asthma as indicated under "Warnings" section on FDA
approved NRT Drug Facts Label.

3. More than weekly use in the past 3 months of illegal drugs or prescription drugs that
are not being used for medically prescribed purposes or inpatient treatment for these
in the past 6 months.

4. Use of non-cigarette nicotine delivery product in the prior week (including cigars,
pipes, chew, snus, hookah, electronic cigarette and marijuana mixed with tobacco).

5. Use of an FDA approved cessation medication in past week (any NRT, Chantix,
Wellbutrin)

6. Women who are pregnant (verified by urine pregnancy test at visit), trying to become
pregnant (not using a medically acceptable form of birth control for at least one
month prior to visit i.e., oral contraceptives, intrauterine device, double barrier),
or nursing.

7. Uncontrolled serious psychiatric illness or inpatient treatment in the past 6 months.

8. Unwillingness to provide blood samples or history of repeatedly fainting during blood
draws

9. Any previous adverse reaction to NRT.

10. Any other condition, serious illness, or situation that would, in the investigator's
opinion, make it unlikely that the participant could comply with the study protocol.