A randomised, open-label, cross-over clinical study to evaluate the pharmacokinetic, pharmacodynamic and safety and tolerability profiles of tobacco-free oral nicotine pouches relative to cigarettes

Abstract

Rationale: Tobacco harm reduction (THR) involves encouraging adult smokers who would otherwise continue to smoke to transition to less harmful forms of nicotine delivery. These products must offer adult smokers reduced exposure to chemicals associated with tobacco combustion, satisfactory blood plasma nicotine levels and serve as an acceptable alternative. The most recent THR innovation is tobacco-free oral nicotine pouches.

Objectives: This study aimed to compare pharmacokinetic, pharmacodynamic and safety and tolerability profiles of two nicotine pouch variants (ZoneX #2 (5.8 mg nicotine/pouch); ZoneX #3 (10.1 mg nicotine/pouch)) with cigarette to assess the pouches' THR potential.

Methods: This was a controlled use, randomised, open-label, cross-over clinical study with 24 healthy adult traditional tobacco users. Pharmacokinetic (plasma nicotine levels; up to 8 h post-use), pharmacodynamic (urge to smoke, product liking; up to 4 h post-use) and short-term safety and tolerability profiles were assessed.

Results: Distinct nicotine pouch pharmacokinetic profiles indicated nicotine absorption via the oral mucosa. Plasma nicotine levels were lower, and time to peak slower, for the nicotine pouches compared to cigarette (Cmax cigarette: 11.6 ng/ml vs. #2: 5.2 ng/ml, p < 0.0001; #3: 7.9 ng/ml, p < 0.0003) (Tmax cigarette: 8.6 min vs. #2: 26 min; #3: 22 min). All products effectively reduced subjects' urge to smoke and presented favourable product liking scores; nicotine pouches were also well tolerated following short-term use (no serious adverse events).

Conclusions: Overall, the assessed ZoneX nicotine pouches may offer an acceptable alternative for adult smokers to achieve satisfactory levels of nicotine delivery and, based on the pharmacokinetic parameters and under the study conditions, likely have a lower abuse liability and addictive potential for current adult smokers compared to continued cigarette smoking.

Clinical trial identifier: NCT04891406 (clinicaltrials.gov).

Keywords: Cigarettes; Nicotine; Nicotine pouches; Oral nicotine delivery; Smoking; Tobacco harm reduction; Tobacco-free nicotine pouches.

Conflict of interest statement

All the authors were employed by Imperial Brands PLC either during part or all of the study. Skruf Snus A.B., Sweden, is a wholly owned subsidiary of Imperial Brands PLC and is the manufacturer of the two nicotine pouch products investigated in this study.

© 2022. The Author(s).

Figures

Fig. 1

Study design overview, where three products: two nicotine pouches (#2 (5.8 mg nicotine/pouch) and #3 (10.1 mg nicotine/pouch)) and one cigarette product, were randomised to 24 subjects for assessments across 5 days

Fig. 2

Baseline adjusted nicotine levels measured in the blood plasma of adult traditional tobacco product users during 8 h following use of a single nicotine pouch product (#2 or #3) or cigarette. For #2, n = 21; #3, n = 22; cigarette, n = 22. Non-baseline adjusted data plotted with error bars (standard deviation) can be found in the supplementary information (Fig. S1)

Fig. 3

Average self-reported urge to smoke according to the 100-mm VAS scoring system self-assessed by subjects over 240 min following use of a single nicotine pouch (#2 or #3) or cigarette study products (pre-dose is plotted as 0 min). 100 = extreme urge to smoke, 0 = no urge to smoke. A lower score indicates a greater reduction in desire to smoke. For no. #2, n = 22; no. #3, n = 23; cigarette, n = 22. Data plotted with error bars (standard deviation) can be found in the supplementary information (Fig. S2)

Fig. 4

Average product liking according to the 100-mm VAS scoring system self-assessed by subjects over 2–240 min following use of a single nicotine pouch (#2 or #3) or cigarette study products. 100 = extreme, 0 = none. A higher score indicates greater product liking. For no. #2, n = 22; no. #3, n = 23; cigarette, n = 22. Data plotted with error bars (standard deviation) can be found in the supplementary information (Fig. S3)