A randomised, open-label, cross-over clinical study to evaluate the pharmacokinetic profiles of cigarettes and e-cigarettes with nicotine salt formulations in US adult smokers

According to Public Health England and the Royal College of Physicians, electronic cigarettes (e-cigarettes) are likely to be at least 95% less harmful than conventional cigarettes [1, 2]. This view was recently reaffirmed, with a further comment from Public Health England that e-cigarettes pose only a fraction of the harms that smoking does, and that smokers should be encouraged to switch [3]. Continuing to recognise that complete cessation of all tobacco and nicotine use as the best action smokers can take to improve their health, Public Health England and the Royal College of Physicians are clear that encouraging and assisting smokers who are neither interested nor willing to quit smoking to switch to using nicotine products that are substantially less harmful than inhaled tobacco smoke is the next best option to help stop smoking [2, 3].

A growing body of evidence suggests that e-cigarettes can be an effective tool in helping smokers to quit smoking [3‐6]. E-cigarettes have become the most common quitting aid for smokers in England, a finding supported by recent data, suggesting that 38.2% of smokers in the last quarter of 2017 reported using an e-cigarette in their recent quit attempt compared with 18% using nicotine replacement therapy (NRT) and 2.8% using Varenicline [3]. Studies investigating abstinence rates have found that e-cigarettes are helpful in enabling smokers to switch and subsequently remain smoke free. For example, a 2016 report estimated that 2.5% of smokers in England who used an e-cigarette in their quit attempt (22,000 people) succeeded where they would have failed if they had used nothing or a licensed nicotine product purchased over the counter [7]. An analysis of the data from the Eurobarometer 429 cross-sectional survey, performed in a representative sample of the European Union 28 Member States in 2014, found that smoking cessation with daily use of e-cigarettes was over 47% [8]. A recent study by Manzoli and colleagues followed up 236 e-cigarette users (all of whom were ex-smokers), 491 smokers, and 232 dual users for 12 months. They reported that 61.9% of the vapers were still abstinent from tobacco smoking after 12 months, compared with just 20.6% of the smokers and 22.0% of the dual users, suggesting that e-cigarettes can be effective in helping smokers abstain [9]. Research undertaken by Polosa and colleagues has also shown that the provision of e-cigarettes to smokers that have expressed no prior commitment to stopping smoking is associated with a significant reduction in smoking prevalence [10].

While there is a growing consensus that e-cigarettes are substantially less harmful than smoking and have the potential to generate substantial public health benefits at a population level if significant numbers of smokers switch from smoking to e-cigarette use [2, 3, 11, 12]; at this time, only minority of smokers have fully switched to vaping. For example, in the UK, there are an estimated 7.4 million adults who continue to smoke [13]. Whilst inaccurate beliefs on the relative harmfulness of e-cigarettes may be deterring many smokers from even trying an e-cigarette [3], it also suggests that currently available e-cigarettes do not provide smokers with the sensory experience they require from their conventional cigarettes [14]. Given the US Food and Drug Administration (FDA) have highlighted the role of nicotine in tobacco products, we hypothesise that the nicotine delivery profile of e-cigarettes may play a major role in consumer-reported satisfaction [15].

Adapting the speed of nicotine delivery from e-cigarettes may assist smokers in fully switching [16]. Nicotine replacement therapies (NRT) such as nicotine gums, patches and inhalators, deliver nicotine much more slowly and at lower doses than conventional cigarettes [3, 15, 17]. In addition to the absence of the behavioural and sensorial aspects of the smoking experience using such products, this may explain the limited success rate of NRT in smoking cessation. Smoking abstinence using NRTs is reportedly less than 7% after 12 months [17]. There have been number of attempts to develop an inhaled product which would deliver nicotine through the lung and mimic the physiological response from smoking. However, many of them produced intolerable aversive reactions or delivered an ineffective dose of nicotine [18]. By contrast, as e-cigarettes have evolved through several technical innovations, their nicotine delivery has also improved, although it has been shown to vary considerably across e-cigarette products [19‐21]. Under the same puffing regime, experienced e-cigarette users can achieve greater increases in blood nicotine levels than naïve users, albeit at a much slower rate than achieved by smoking a conventional cigarette [20, 22]. E-cigarette nicotine intake and delivery have also been shown to be related to, and influenced by, user puffing topographies [1, 2, 23, 24], which differ significantly from puffing behaviours associated with smoking [25, 26]. When focussing on experienced e-cigarette users, it has been shown that comparable or higher blood nicotine levels can be obtained compared to smoking [27, 28]. A recent pharmacokinetic study also found that similar doses and speed of nicotine delivery to conventional cigarettes can be achieved among users of more modern advanced tank e-cigarette devices [29].

The form of nicotine ordinarily used in e-liquids is termed as ‘freebase’ nicotine. Freebase nicotine is volatile. As a result, when an e-cigarette aerosol is inhaled by a user, the nicotine is more likely to off-gas from the aerosol droplets and deposit in the mouth/upper respiratory tract, where it is absorbed into the blood. Absorption in the oral cavity/upper respiratory tract is slower than that with conventional cigarette with pharmacokinetic studies indicating a profile which more closely resembles NRT than a conventional cigarette [18]. The need for more effective and appealing e-cigarette products to provide satisfying alternatives to smoking has led to the recent development and marketing of e-liquids containing ‘nicotine salts’. Nicotine salts are formed by the reaction of nicotine with a suitable acid and are less volatile than freebase nicotine [15]. As a result, a greater fraction of the nicotine in the salt form would be expected to remain in inhaled aerosol droplets until the aerosol reaches the alveoli for pulmonary absorption. For pulmonary absorption, once deposited, nicotine salts must first dissociate into freebase and acid, to enable the non-polar, lipid-soluble freebase nicotine to gain cellular entry at the alveoli [15]. If nicotine salts can more closely replicate cigarette-like nicotine delivery in the lung, they should enable switching to e-cigarettes, therefore helping to further realise the harm reduction potential of these products.

Currently, there are limited data in the published literature available on the pharmacokinetic profiles of e-cigarettes containing nicotine salts. Here we performed a randomised, open-label, six-period cross-over clinical study to evaluate the nicotine uptake from two e-cigarette device platforms with varying concentrations of nicotine lactate (nicotine salt) or freebase nicotine e-liquids relative to conventional cigarettes in US adult smokers. In addition, subjective effects and tolerability of the tested products were also assessed.

This study provides new insights into e-cigarette products that contain nicotine lactate when used by adult smokers under controlled conditions. The data indicate that nicotine in lactate salt formulation is rapidly delivered into the systemic circulation following inhalation using nicotine lactate e-cigarette products with plasma pharmacokinetic profiles consistent with pulmonary absorption; however, with nicotine doses less than that of a conventional cigarette. Compared to conventional cigarettes, exposure to nicotine was 41% lower following use of myblu 40 mg (nicotine lactate), 60% lower following use of myblu 25 mg (nicotine lactate), 63% lower following use of myblu 16 mg (nicotine lactate), and 70% lower following use of myblu 25 mg (freebase). The blu PRO 48-mg (nicotine lactate) product delivered approximately 73% less nicotine compared to conventional cigarettes.

As might be expected, variations in the concentration of nicotine content of the e-liquid also had an impact on nicotine delivery. Indeed, the pharmacokinetic profile of the 40-mg nicotine lactate e-cigarette product was approaching that of a conventional cigarette; whereas, the 16-mg comparator was significantly different. The subjective data also show that the 40-mg nicotine lactate product reduced the desire to smoke numerically more than the 16-mg nicotine lactate product; this may be consistent with an efficient transfer of more nicotine to the lungs and a rapid rise of nicotine absorption in the plasma. These initial findings suggest that e-cigarettes with a higher concentration of nicotine in nicotine lactate form may be more effective and more appealing products for adult smokers switching from cigarettes to vapour products. This is in line with public health recommendations in the UK and elsewhere, e.g. [3, 12, 35].

From smoking a conventional cigarette, a plasma nicotine concentration of around 4 ng/mL has been reported to occupy up to 90% of available α4β2* nicotinic acetylcholine receptors in the brain and significantly reducing desire to smoke [36]. By contrast, following use of a licensed nicotine inhaler, a peak receptor occupancy of 60% is only reached after 3 h which was insufficient to reduce desire to smoke [37]. Thus, it appears that a shorter T_max is important to activate most nicotine receptors and provide smoker satisfaction from alternative products. In our study, the T_max values for all e-cigarettes were in a range which is comparable to published conventional cigarette data [38]. A study is underway to assess smoking reduction and switch rates associated with nicotine lactate e-cigarette ad libitum use in the real-world with medicinal nicotine replacement product and freebase e-cigarette comparators.

The European Union Tobacco Products Directive (EUTPD) mandates that the maximum nicotine content of an e-liquid cannot exceed 20 mg/mL. Recent research has shown that the use of lower nicotine concentration e-liquids may be associated with ‘compensatory behaviour’ as e-cigarette users puff more deeply, more frequently and for longer to obtain a level of nicotine that reduces desire to smoke [39]. In the present study, the myblu 40-mg nicotine lactate product had the closest nicotine uptake profile to the conventional cigarette with the greatest relief in desire to smoke. However, this product would not be permitted in the European Union. Both Public Health England and the Royal College of Physicians have stated that the cap on nicotine concentrations imposed by the EUTPD may limit the effectiveness of e-cigarettes as a smoking substitute, particularly for heavier smokers [1, 2]. Based on our initial data presented here, and other research insights [40], the EUTPD nicotine concentration limit should be reviewed in line with the scientific literature to ensure that adult smokers have ready access to better alternatives that reduce desire to smoke. Higher nicotine strength liquids with nicotine lactate formulations and suitable flavour options that can be marketed to smokers may maximise the public health potential of e-cigarettes.

This was a small, short-duration study that was not designed to fully evaluate safety. However, reports of AEs were recorded, and the study was conducted to GCP. Use of the nicotine lactate e-cigarettes was well tolerated by the participants with no severe or serious AEs and no participants discontinued the study owing to an AE.

The main limitation of this study is that the e-cigarette puff profile was fixed (use was not ad libitum) to obtain clear pharmacokinetic profiles and blood sampling was collected for only 30 min. A more robust pharmacokinetic assessment is planned in future studies. It is likely that smokers using the e-cigarette devices in the ‘real world’ would change their behaviour to adapt to the new products and own preference. To assess the amount of nicotine and smoker satisfaction that nicotine lactate e-cigarettes provide under real-world conditions, it would be beneficial to conduct a long-term study that allows subjects to adapt their behaviour to product use. Another limitation is that study participants were not experienced e-cigarette users. However, prior to study start, subjects could use each of the products, although their preferences on the products ahead of the study start were not known. This may have influenced the reporting of subjective effects. The e-cigarette products may not have been used in an optimal way or in the same way they would have been used had the participants been familiar with the product; a longer familiarisation training period would be beneficial in future studies. Furthermore, only tobacco-flavoured e-cigarettes were assessed in this study; had the participants the opportunity to vary the flavour it may have influenced product use and satisfaction. In the present study, only nicotine lactate salt formulations were assessed; further research is also warranted to determine the pharmacokinetic profiles and efficacy of other nicotine salt formulations.

In summary, the results of this study indicate that the use of nicotine lactate in e-cigarettes has promise as an effective form of nicotine replacement. The pharmacokinetic and subjective data demonstrate that nicotine lactate can be used to deliver nicotine via the pulmonary route for increased speed of absorption, albeit with a maximum nicotine level that did not exceed the conventional cigarette, coupled with acceptable subjective satisfaction and relief of desire to smoke. Further studies are warranted to fully assess the efficacy of nicotine lactate in aiding smokers to fully switch to e-cigarettes in the real-world, as well as the research on the role of flavours and other innovations that can maximise the public health potential of alternatives to cigarettes for adult smokers.