A Study to Assess the Nicotine Pharmacokinetics, Tolerability and Safety With a New Oral Nicotine Replacement Product in Healthy Japanese Smokers

Study arms

• Experimental
  Part 1; Treatment Sequence ABDC

  Participants will receive Treatment A (one spray of oromucosal nicotine spray \[ONS\]) at Visit 1, then Treatment B (2 consecutive sprays of ONS at Visit 2, then Treatment D (1 cigarette \[10 puffs\]) at Visit 3, followed by Treatment C (nicotine gum) at Visit 4. The visits will be separated by a period of at least 7 calendar days.

  Drug: Oromucosal Nicotine Spray (ONS) · Drug: Nicotine Gum · Other: Cigarette

• Experimental
  Part 1; Treatment Sequence BCAD

  Participants will receive Treatment B at Visit 1, then Treatment C at Visit 2, then Treatment A at Visit 3 followed by Treatment D at Visit 4. The visits will be separated by a period of at least 7 calendar days.

  Drug: Oromucosal Nicotine Spray (ONS) · Drug: Nicotine Gum · Other: Cigarette

• Experimental
  Part 1; Treatment Sequence CDBA

  Participants will receive Treatment C at Visit 1, then Treatment D at Visit 2, then Treatment B at Visit 3 followed by Treatment A at Visit 4. The visits will be separated by a period of at least 7 calendar days. The visits will be separated by a period of at least 7 calendar days.

  Drug: Oromucosal Nicotine Spray (ONS) · Drug: Nicotine Gum · Other: Cigarette

• Experimental
  Part 1; Treatment Sequence DACB

  Participants will receive Treatment D at Visit 1, then Treatment A at Visit 2, then Treatment C at Visit 3 followed by Treatment B at Visit 4. The visits will be separated by a period of at least 7 calendar days.

  Drug: Oromucosal Nicotine Spray (ONS) · Drug: Nicotine Gum · Other: Cigarette

• Experimental
  Part 2; Treatment Sequence EF

  Participants who complete Part 1 will be selected for Part 2 based on the results of genetic polymorphism test and other examinations. Selected participants will receive Treatment E (two consecutive sprays of ONS once every 30 minutes until 11.5 hours) at Visit 5, followed by Treatment F (two consecutive sprays of ONS once every 1 hour until 11 hours) at Visit 6. The visits will be separated by a period of at least 7 calendar days.

  Drug: Oromucosal Nicotine Spray (ONS)

• Experimental
  Part 2; Treatment Sequence FE

  Participants who complete Part 1 will be selected for Part 2 based on the results of genetic polymorphism test and other examinations. Selected participants will receive Treatment F at Visit 5 followed by Treatment E at Visit 6. The visits will be separated by a period of at least 7 calendar days.

  Drug: Oromucosal Nicotine Spray (ONS)

Interventions

• DrugOromucosal Nicotine Spray (ONS)

  Participants will receive oral dose of oromucosal nicotine spray (ONS).

• DrugNicotine Gum

  Participants will chew nicotine gum for 30 minutes.

• OtherCigarette

  Participants will smoke one cigarette as 10 puffs for 3 minutes.

Primary outcomes

1. Part 1: Maximum Baseline Corrected Plasma Nicotine Concentration (cCmax)

   cCmax is defined as the maximum baseline corrected plasma nicotine concentration (cCmax).

   Time frame: Predose; 2, 4, 6, 8, 10, 15, 20, 30, 45 and 60 minute (min) and 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose

2. Part 1: Baseline Corrected Area Under the Plasma Nicotine Concentration versus (vs) Time Curve Until the Last Measurable Time Point (cAUCt)

   cAUCt is defined as the baseline corrected area under the plasma nicotine concentration-vs time curve until the last measurable time point.

   Time frame: Predose; 2, 4, 6, 8, 10, 15, 20, 30, 45 and 60 min and 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose

3. Part 1: Baseline Corrected Area Under the Plasma Nicotine Concentration-vs Time Curve Extrapolated to Infinite (cAUC[infinity])

   cAUC(infinity) is defined as the baseline corrected area under the plasma nicotine concentration-vs time curve extrapolated to infinite.

   Time frame: Predose; 2, 4, 6, 8, 10, 15, 20, 30, 45 and 60 min and 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose

4. Part 1: Baseline Corrected Area Under the Plasma Nicotine Concentration-vs Time Curve until the Last Measurable Time Point (cAUCt)

   cAUCt is defined as baseline corrected area under the plasma nicotine concentration-vs time curve until the last measurable time point.

   Time frame: Predose; 2, 4, 6, 8, 10, 15, 20, 30, 45 and 60 min and 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose

5. Part 2: Average Plasma Nicotine Concentration During the Last Dosing Interval/Intervals (Cav)

   Cav is defined as the average plasma nicotine concentration during the last dosing interval/intervals.

   Time frame: Predose, 2, 4, 6, 8, 10, 15, 20, 30 post last dose (last dose: Hour 11.5 for Treatment E and Hour 11 for Treatment F); 45 and 60 min post last dose for Treatment F

6. Part 2: Area Under the Plasma Nicotine Concentration-vs Time Curve During the Last Dosing Interval/Intervals (AUCtau)

   AUCtau is defined as the area under the plasma nicotine concentration-vs time curve during the last dosing interval/intervals.

   Time frame: Predose, 2, 4, 6, 8, 10, 15, 20, 30 post last dose (last dose: Hour 11.5 for Treatment E and Hour 11 for Treatment F); 45 and 60 min post last dose for Treatment F

7. Part 2: Maximum Plasma Nicotine Concentration During the Last Dosing Interval/Intervals (Cmax)

   Cmax is defined as maximum observed plasma nicotine concentration.

   Time frame: Predose, 2, 4, 6, 8, 10, 15, 20, 30 post last dose (last dose: Hour 11.5 for Treatment E and Hour 11 for Treatment F); 45 and 60 min post last dose for Treatment F

Secondary outcomes

1. Part 1: Area Under the Plasma Nicotine Concentration-vs Time Curve until 10 Minutes after Start of Administration [AUC10min],

   AUC10min is defined as the area under the plasma nicotine concentration-vs time curve until 10 minutes after start of administration.

   Time frame: Predose; 2, 4, 6, 8, 10 min postdose

2. Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax)

   Tmax is defined as actual sampling time to reach maximum observed analyte concentration.

   Time frame: Predose; 2, 4, 6, 8, 10, 15, 20, 30, 45 and 60 min and 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose

3. Part 1: Terminal Half-Life [t1/2]

   Terminal half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).

   Time frame: Predose; 2, 4, 6, 8, 10, 15, 20, 30, 45 and 60 min and 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose

4. Part 1: Terminal Elimination Rate Constant (Lambda[z])

   Lambda (z) is apparent terminal elimination rate constant, determined by linear regression using the terminal log-linear phase of the log transformed concentration-time curve.

   Time frame: Predose; 2, 4, 6, 8, 10, 15, 20, 30, 45 and 60 min and 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose

5. Part 2: Minimum Plasma Nicotine Concentration During the Last Dosing Interval/Intervals (Cmin)

   Cmin is defined as the minimum plasma nicotine concentration during the last dosing interval/intervals.

   Time frame: Predose, 2, 4, 6, 8, 10, 15, 20, 30 post last dose (last dose: Hour 11.5 for Treatment E and Hour 11 for Treatment F); 45 and 60 min post last dose for Treatment F

6. Part 2: Peak-Trough Fluctuation [PTF]

   PTF calculated by 100\*(Cmax - Cmin)/Cav will be assessed.

   Time frame: Predose, 2, 4, 6, 8, 10, 15, 20, 30 post last dose (last dose: Hour 11.5 for Treatment E and Hour 11 for Treatment F); 45 and 60 min post last dose for Treatment F

7. Part 2: Swing

   Swing will be calculated as (Cmax - Cmin)/Cmin.

   Time frame: Predose, 2, 4, 6, 8, 10, 15, 20, 30 post last dose (last dose: Hour 11.5 for Treatment E and Hour 11 for Treatment F); 45 and 60 min post last dose for Treatment F

8. Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax)

   Tmax is defined as actual sampling time to reach maximum observed analyte concentration.

   Time frame: Predose, 2, 4, 6, 8, 10, 15, 20, 30 post last dose (last dose: Hour 11.5 for Treatment E and Hour 11 for Treatment F); 45 and 60 min post last dose for Treatment F

9. Part 1 and Part 2: Number of Participants with Adverse Events (AEs)

   An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

   Time frame: Up to 4 months