We evaluated PK parameters of four flavor variants of e-liquids used in Vuse Solo ENDS with 4.8% (57 mg/mL) nicotine content by weight following an acute exposure in predominately ENDS naïve smokers. Our data showed that subjects achieved similar overall nicotine exposure (AUCnic0−60), maximum plasma nicotine concentrations (Cmax), and time to maximum concentrations (Tmax) while using one of the four flavor variants of Vuse Solo ENDS. Evaluation of PK parameters, Cmax and AUCnic0−60, showed similar nicotine uptake distribution patterns across all flavors variants with overlap of the 95% confidence intervals (CIs) around the medians in both Cmax and AUCnic0−60 (illustrated as the notches in boxplots, Figures 2 and 3). In addition to the PK assessments, product liking (OPL) for each flavor was assessed at the 13-minute timepoint (Table 3).
As stated above, the results and distribution of baseline-adjusted Cmax were similar across flavor variants. By comparison, baseline-adjusted maximum nicotine concentrations (Cmax) of Vuse Solo flavor variants in this study are higher (Table 2) than those previously reported by Stiles et. al. using Vuse Solo ENDS Original (tobacco) 15 and Vuse Solo ENDS Menthol 16; for reference, the 29 mg nicotine e-liquid used in the Stiles et. al. papers corresponds to roughly the same nicotine concentrations (57 mg/ml or 4.8%) as was used in the current study. It is important to note key differences among study designs of the abuse liability studies performed by the Stiles et. al. papers and the current study. The former studies utilized a crossover design (Williams design) and were conducted in an ambulatory setting. In contrast, our study utilized a parallel design in confinement. Both Stiles AL studies had approximately 7 days of at-home product acclimation as our study with instruction to use ENDS IP at least once but product use compliance was not assessed. In our study, subjects were told to use the ENDS IPs as often as they liked, and product use compliance was confirmed by weighing used cartridges at the end of the at-home trial period. Thus, differences in study design as well as level of familiarity with study products and general differences between study populations may account for variability among data reported. In a study to evaluate the abuse liability (AL) of ENDS in experienced ENDS users by Hajek and colleagues 17, Vuse Solo Original 4.8% was evaluated as one of the ENDS comparators and the results demonstrated that Vuse Solo Original 4.8% users achieved baseline-adjusted Cmax of 13.6 ng/ml ( 9.7 SD), which is higher than what was found in the current study, but still lower than the Cmax reported for cigarettes (17.9 ng/ml [16 SD]). In contrast, in an AL study of cigarette smokers conducted by Goldenson and colleagues 18, the authors reported that Vuse Solo Original 4.8% had a baseline-adjusted Cmax of 6.8 ng/ml, which was similar to our study findings, and lower than cigarette Cmax (15.4 ng/ml). Similarly, another AL study by Campbell et. al., with a similar subject population as the current study, reported a mean baseline-adjusted Cmax for Vuse Solo Original 4.8% as 5.48 ng/mL 13. Additional results from other AL studies also suggest that experienced users of ENDS demonstrate higher nicotine uptake, compared to naïve ENDS users, but in general the Cmax following acute exposure to ENDS was less than that observed with smoking a cigarette, regardless of the ENDS use experience 13,19−25.
As was the case with Cmax, baseline-adjusted AUCnic0−60 results and their distribution were also similar across Vuse Solo flavor variants. There are limitations in comparing the overall nicotine exposure, AUCnic0−60, between the current study against published works due to the differences in AUC calculations performed across studies based on the duration of observation 15–17. Goldenson et al., in an AL study among cigarette smokers, reported a baseline-adjusted AUCnic0−60 of 216 min*ng/ml for Vuse Solo Original 4.8%, which is similar to the AUCnic0−60 for Vuse Solo Original in this study of 223.79 min*ng/ml 18. Taken together, the PK findings from this reported study are in agreement with previously published data using Vuse Solo ENDS 15–18.
In addition to PK assessments, subjects were also asked to rate OPL for the Vuse Solo flavor variants on an 11-point NRS. Subjects rated the Tropical flavor highest and rated the Mint flavor lowest with Original (tobacco) and Fusion flavors in-between (Table 3). These reported scores were consistent with published data. In two AL studies by Stiles et. al., subjects assessed product liking scores for two flavors (Vuse Original and Menthol) at multiple timepoints over six hours after start of ENDS use. In both studies by Stiles et. al., maximum PL scores (Emax) for Vuse Solo Original and Menthol (36 mg/ml nicotine) were reported at 4.13 and 4.53, respectively 15,16, compared to 6.4 and 5.3 for Vuse Solo Original and Mint 4.8% (57 mg/ml nicotine) reported in this study. Similarly, in the AL studies by Goldenson et. al., and Campbell et. al., where Vuse Solo Original 4.8% was used as an ENDS comparator, mean maximum product liking scores were between 4.5 and 5, and 5.56, respectively 13,18.
Review of our data on e-liquid consumption measured by cartridge weight before and after PK test sessions in the context of OPL scores suggest some trends but failed to show a direct linear correlation. St. Helen and colleagues examined the impact of flavors (Strawberry vs. tobacco) on nicotine uptake and topography. The authors found no statistically significant differences in PK parameters and in puffing behavior and noted the need for further investigation 26,27. Of note, these differences were seen in subjects who used fruity/sweet flavored e-liquids in their own ENDS products, suggesting potential subject bias towards flavors that resembled their usual flavors.
Similarly, in a topography study to assess the effect of flavor in regular smokers, Voos et al., concluded that the flavors used in their study delivered differential amounts of nicotine, potentially associated with product use topography, and differences in subjective effects are not solely a product of nicotine delivery, and recommended additional research 28. In contrast, Cobb et. al., assessed subjective effects among young adult smokers using ENDS with three flavors (cream, tropical fruit and tobacco/menthol) at nicotine concentrations ranging from 0 to 36 mg/ml nicotine and concluded that e-liquid flavors did not appear to have significant impact on subjective effects 29. Thus, the implications of overall product liking scores on both PK parameters and e-liquid consumption may require additional studies to further evaluate any potential relationship.
In our study, subjects were asked to familiarize themselves with ENDS products at home for one week prior to a PK test session, and the amount of e-liquid consumed was measured by differences in cartridges weights obtained before and after a week of at home use. We found that our subjects used approximately 10% of e-liquid by weight ranging from 0.16 (+/- 0.17) mg to 0.21 (+/- 0.25) mg across the four flavors (Table 1). These results were similar to e-liquid consumption observed on the first day of exclusive ENDS use in a biomarker of exposure study by Round and colleagues 8 and suggests that our ENDS naïve subjects were sufficiently acclimated to ENDS IPs during their at-home trial period prior to the PK test sessions.
Our study had several strengths. First, we included a large sample size to reduce variability compared to previous ENDS nicotine PK studies 23,30−34. In addition, our subjects were required to acclimate to ENDS for seven days to become familiar with ENDS products prior to confinement and PK test sessions. Subjects were also required to abstain from tobacco products for 12 hours prior to PK test sessions to ensure their blood nicotine concentrations were close to baseline prior to the start of product use. Furthermore, we collected blood samples at intervals that allowed characterization of nicotine PK following ad libitum ENDS exposure and the nicotine concentrations of blood samples were baseline-adjusted to ensure more accurate results.
Despite these strengths, the study had several limitations. Although we allowed participation of dual users, more than 98% of our subjects were exclusive cigarette smokers. As the prevalence of dual and poly use of multiple types of tobacco and nicotine products, such as ENDS or other non-combustible nicotine products, continues to increase, inclusion of a greater proportion of dual users of CC and ENDS in future studies may be useful to make study findings more applicable to current nicotine and tobacco users. Future studies may also benefit from cross-over designs to evaluate nicotine PK with multiple flavor variants to reduce inter-user variability. Lastly, for this study, subjects were allowed a 10-minute ad libitum use of the ENDS 15,16,24,28,33,34. We chose the duration of 10-minutes of ENDS use to align with an estimated duration to smoke a single CC. However, this study design element may be modified in the future studies to align more closely with historical data on the time it takes to smoke a single CC, as well as current data trends around ENDS topography. Moreover, other considerations might include current reports on the time for subjects to smoke a single CC 18,35,36 or recent study designs which leverage a shorter ENDS use period 17,22,29,31,32,37−42.
In conclusion, the primary endpoints of this study, Cmax and AUCnic0−60, were similar across all four flavors as evidenced by the overlap of 95% confidence intervals, suggesting that flavors are not significant factors in nicotine exposure in an acute exposure setting. The results of this study will add to the growing body of literature regarding the effects of flavors on nicotine delivery and uptake.