Multiple Dose, Dose Escalation Study of Varenicline Controlled Release Formulation in Adult Smokers

• Pharmacokinetic endpoints include varenicline area under the curve from 0-24 hours (AUC24), maximum plasma concentration (Cmax), [ Time Frame: Day 1 and Day 14 ] [ Designated as safety issue: No ]
• Safety endpoints include evaluation of clinical safety laboratory tests, supine vital signs, triplicate 12-lead ECGs and adverse events. [ Time Frame: up to 14 days ] [ Designated as safety issue: Yes ]
• Time of maximum plasma concentration (Tmax) on Day 1 and Day 14 [ Time Frame: Day 1 and Day 14 ] [ Designated as safety issue: No ]
• Minimum plasma concentration (Cmin), terminal half life (t1/2), observed accumulation ratio (Rac), peak:trough fluctuation (%PTF) on Day 14 only. [ Time Frame: Day 14 ] [ Designated as safety issue: No ]

• Pharmacokinetic endpoints include varenicline area under the curve from 0-24 hours (AUC24), maximum plasma concentration (Cmax), and time of maximum plasma concentration (Tmax) on Day 1 and Day 14
• Safety endpoints include evaluation of clinical safety laboratory tests, supine vital signs, triplicate 12-lead ECGs and adverse events
• Minimum plasma concentration (Cmin), terminal half life (t1/2), observed accumulation ratio (Rac), and peak:trough fluctuation (%PTF) on Day 14 only

The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of escalating multiple oral doses of varenicline AMT 8 controlled release formulation for 14 days in adult smokers.

• Drug: Varenicline Tartrate
  Varenicline 1.8 mg AMT-8 controlled release tablets administered twice a day for 14 days.
• Drug: Varenicline Tartrate
  Planned dose is Varenicline 2.4 mg AMT-8 controlled release tablets administered twice a day for 14 days. Actual dose may be adjusted based on emerging data from prior dose cohorts.
• Drug: Varenicline Tartrate
  Planned dose is Varenicline 3 mg AMT-8 controlled release tablets administered twice a day for 14 days. Actual dose may be adjusted based on emerging data from prior dose cohorts.
• Drug: Varenicline Tartrate
  The dose to be administered is not yet determined and will be based on emerging data from prior dose cohorts. The dose will be administered as Varenicline AMT-8 controlled release tablets twice a day for 14 days. The doses to be tested may be lower, higher or repeat a previously tested dose and may include a titration.

• Cohort 1
  Subjects will be randomized to receive either experimental drug (N=9) or matching placebo (N=3).
  Intervention: Drug: Varenicline Tartrate
• Cohort 2
  Subjects will be randomized to receive either experimental drug (N=9) or matching placebo (N=3).
  Intervention: Drug: Varenicline Tartrate
• Cohort 3
  Subjects will be randomized to receive either experimental drug (N=9) or matching placebo (N=3).
  Intervention: Drug: Varenicline Tartrate
• Optional Cohort 4
  Subjects will be randomized to receive either experimental drug (N=9) or matching placebo (N=3).
  Intervention: Drug: Varenicline Tartrate
• Optional Cohort 5
  Subjects will be randomized to receive either experimental drug (N=9) or matching placebo (N=3).
  Intervention: Drug: Varenicline Tartrate

Inclusion Criteria:

• Healthy male and/or female subjects between the ages of 18 and 55 years, inclusive. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12 lead ECG and clinical laboratory tests.
• Currently smoking and have smoked an average of at least 10 cigarettes per day during the past year, with no period of abstinence greater than 3 continuous months in the past year.

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
• Pregnant or nursing women are excluded; women of childbearing potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception as outlined in the protocol from at least 14 days prior to study medication administration until completion of protocol-required procedures are excluded.
• Subjects with an estimated creatinine clearance (CLcr) <80 mL/min derived using the method of Cockcroft and Gault.