This study will assess the bioequivalence of the test product (Nicotine Prototype Mini lozenge 4 milligrams \[mg\]) to a commercial reference product (nicotine polacrilex mini lozenge 4mg) in healthy smokers under fasting conditions.
This study will be a single center, randomized, open label, single dose, two-way crossover in healthy smokers that smoke their first cigarette within 30 minutes of waking. This study will consist of following Visits: Visit 1 (Screening), Visit 2 (Study Period 1), followed by a Washout period and Visit 3 (Study Period 2). This will ensure approximately 29 evaluable participants per treatment arm. Each participant will be treated with a single dose of the two study treatments (test and reference) in a randomized sequence, under fasting conditions. Participants will be confined in the study facility for approximately 60 hours during each study session (for 36 hours pre-dosing and for 24 hours post dosing) during which pharmacokinetic (PK) blood samples will be obtained. Participants are to abstain from smoking during the confinement periods and be subject to random measurements of expired carbon monoxide (CO) to confirm abstinence. The CO levels must be ≤10 parts per million (ppm) throughout the study session. There will be at least 5-day and not more than 7-day clinical furlough period between treatment periods. For each treatment period, the clinical confinement period with restriction of smoking is at least 36 hours prior to dosing.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
37
A single dose of a prototype nicotine 4mg lozenge will be placed in participants mouth, occasionally moving it side to side. Allowing it to slowly dissolve and try to minimize swallowing. Participants will be instructed not to chew lozenge. The lozenge should be completely dissolved.
A single dose of a 4 mg nicotine polacrilex mini lozenge (Nicorette Minis) will be placed in participants mouth, occasionally moving it side to side. Allowing it to slowly dissolve and try to minimize swallowing. Participants will be instructed not to chew lozenge. The lozenge should be completely dissolved.
GSK Investigational Site
Lincoln, Nebraska, United States
Assessment of Bioequivalence of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Area Under the Plasma Concentration Versus Time Curve From Time Zero to Time t (AUC [0-t])
Bioequivalence of prototype mini lozenges with nicorette mini lozenge was assessed by measuring AUC(0-t), where t= time of the last measurable plasma concentration. AUC(0-t) was calculated using the linear trapezoidal with linear interpolation method. A linear mixed-effects model was fit to the natural log (ln)-transformed PK variable (AUC0-t), as the dependent variable, and treatment, period, and sequence as fixed effects. Participant nested within sequence was a random effect. The treatment difference and its 90% CI were exponentiated to obtain the geometric mean ratios (GMR) between the test and reference products and its 90% CI. Geometric Coefficient of variation was provided as percentage.
Time frame: 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period
Assessment of Bioequivalence of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Area Under the Plasma Concentration Versus Time Curve Calculated From Time Zero to Infinity (AUC [(0-inf])
Bioequivalence of prototype mini lozenges with nicorette mini lozenge was assessed by measuring AUC(0-inf). AUC(0-inf) = AUC0-t + (Clast/kel), where, AUC0-t= area under the plasma concentration versus time curve from time zero to time t; Clast= last observed/measured plasma concentration and kel= elimination rate constant. A linear mixed-effects model was fit to the natural log (ln)-transformed PK variable (AUC\[0-inf\]), as the dependent variable, and treatment, period, and sequence as fixed effects. Participant nested within sequence was a random effect. The treatment difference and its 90% CI were exponentiated to obtain the GMR between the test and reference products and its 90% CI. Geometric Coefficient of variation was provided as percentage.
Time frame: 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period
Assessment of Bioequivalence of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Maximum Observed Plasma Nicotine Concentration (Cmax)
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Blood samples were collected at designated timepoints. Bioequivalence of prototype mini lozenges with nicorette mini lozenge was assessed by measuring Cmax that was taken directly from bioanalytical data. Geometric Coefficient of variation was provided as percentage. A linear mixed-effects model was fit to the natural log (ln)-transformed PK variable (Cmax) as the dependent variable, and treatment, period, and sequence as fixed effects. Participant nested within sequence was a random effect. The treatment difference and its 90% CI were exponentiated to obtain the GMR between the test and reference products and its 90% CI. Geometric Coefficient of variation was provided as percentage.
Time frame: 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period
Comparison of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Time of Maximum Plasma Nicotine Concentration (Tmax)
Tmax was defined as the time to maximum plasma nicotine concentration. If the maximum value occurred at more than one time point, Tmax was defined as the first time point with this value.
Time frame: 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period
Comparison of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Apparent Elimination Half-Life (t1/2)
t1/2 was defined as apparent elimination half-life that was calculated as t1/2 = ln(2) / Kel, where Kel= elimination rate constant.
Time frame: 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period
Comparison of Prototype Mini Lozenges With Nicorette Mini Lozenge by Measuring Apparent Elimination Rate Constant for Plasma Nicotine (Kel)
kel was defined as apparent elimination rate constant for plasma nicotine that was calculated as negative of the slope of a linear regression of the log(concentration)- time for all concentrations \> lower limit of quantification.
Time frame: 0.75, 0.5, 0.25 hours predose and 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours postdose in each treatment period
Number of Participants With Clinically Significant Change in Laboratory Test Values
Haematological, biochemistry and urinalysis parameters were analyzed. Clinical significance was judged by the investigator based upon the out of range values of standard range set for each parameter.
Time frame: From signing of the informed consent form until 5 days after last administration of study drug (up to Day 13)