Nicotine flux and pharmacokinetics-based considerations for early assessment of nicotine delivery systems

Abstract

In the past few years, technological advancements enabled the development of novel electronic nicotine delivery systems (ENDS). Several empirical measures such as "nicotine flux" are being proposed to evaluate the abuse liability potential of these products. We explored the applicability of nicotine flux for clinical nicotine pharmacokinetics (PK) and 52-week quit success from cigarettes for a wide range of existing nicotine delivery systems. We found that the differences in nicotine flux for various nicotine delivery systems are not related to changes in PK, as nicotine flux does not capture key physiological properties such as nicotine absorption rate. Further, the 52-week quit success and abuse liability potential of nicotine nasal sprays (high nicotine flux product), and nicotine inhalers (nicotine flux similar to ENDS) are low, suggesting that nicotine flux is a poor metric for the assessment of nicotine delivery systems. PK indices are more dependable for characterizing nicotine delivery systems, and a nicotine plasma $\frac{C_{\max }}{T_{\max }}$ > 1 could improve 52-week quit success from cigarettes. However, a single metric may be inadequate to fully assess the abuse liability potential of nicotine delivery systems and needs to be further studied. A combination of in vitro and in silico approaches could potentially address the factors influencing the inhaled aerosol dosimetry and resulting PK of nicotine to provide early insights for ENDS assessments. Further research is required to understand nicotine dosimetry and PK for ad libitum product use, and abuse liability indicators of nicotine delivery systems. This commentary is intended to (1) highlight the need to think beyond a single empirical metric such as nicotine flux, (2) suggest potential PK-based metrics, (3) suggest the use of in vitro and in silico tools to obtain early insights into inhaled aerosol dosimetry for ENDS, and (4) emphasize the importance of considering comprehensive clinical pharmacology outcomes to evaluate nicotine delivery systems.

Keywords: Electronic nicotine delivery systems; Nicotine dose; Nicotine flux; Nicotine pharmacokinetics; abuse liability.

Graphical abstract

Fig. 1

Influence of (a) nicotine dose and (b) product usage time on nicotine flux for products administered by different administration routes.

Fig. 2

Nicotine flux and pharmacokinetic parameter ($\frac{C_{\max }}{T_{\max }}$) calculated based on plasma concentrations for various nicotine-containing products delivered by different routes; data were obtained from multiple sources as listed in the Supplementary Information.

Fig. 3

Association of (a) nicotine flux and (b) the pharmacokinetic parameter ($\frac{C_{\max }}{T_{\max }}$) of various nicotine-containing products on 52-week quit success from combustible cigarette smoking. The shaded region is the 95% confidence interval for predictions of the linear model (solid line); data were obtained from multiple sources as listed in the Supplementary Information.