Nicotine delivery as a regulatory target
Nicotine delivery and the regulatory landscape
The past few years have seen a rapid growth in the number of smoke-free products, including novel electronic nicotine delivery systems (ENDS). ENDS products, such as e-cigarettes, can be designed to give users a degree of control over the experience, including flavor choices and nicotine strengths. For example, e-cigarette design features, including battery, e-liquid composition, nicotine strength and protonation, can all affect nicotine delivery to the user.
This presents several challenges for public health policy, including the question of how to accurately measure nicotine delivery across different devices and how best to regulate ENDS products for abuse liability (defined by the U.S. Food and Drug Administration (FDA) as “the likelihood that individuals will develop physical and/or psychological dependence on the tobacco product”).
Regulatory agencies have adopted different approaches to these challenges. For example, the FDA has proposed that premarket tobacco product applications (PMTA) for ENDS contain reports of investigations into the abuse liability of new products.
Other regulatory bodies are focused on limiting nicotine concentrations in ENDS devices. For example, the European Union’s Tobacco Products Directive restricted e-liquid nicotine concentration to 20 mg/mL stating, “This concentration allows for a delivery of nicotine that is comparable to the permitted dose of nicotine derived from a standard cigarette during the time needed to smoke such a cigarette.” At the same time, Canadian authorities set the limit to 66 mg/mL based on the toxicological assessment of nicotine.
Nicotine flux, which describes the rate of nicotine emitted from a device (microgram/second), has been proposed as a regulatory tool for potentially limiting the abuse liability of ENDS. For this to be a viable regulatory target, it assumes a direct relationship between nicotine emission from a device and nicotine delivery to the user, and that a high flux product has the same abuse liability as a low flux product.
To analyze if increases in nicotine flux correspond with a rapid rise in systemic nicotine exposure, and what effect this might have on abuse liability outcomes, PMI researchers evaluated existing data from studies on clinical nicotine pharmacokinetics (PK) for products with different modes of delivery/use. The results indicate that nicotine flux, by itself, is a poor indicator of human exposure to nicotine.
What is nicotine flux?
Nicotine flux is a measurement used to describe the rate of nicotine emitted by a nicotine delivery system, including cigarettes and heat-not-burn (HnB) products, over a period of time. Historically, the measurement of nicotine yield, rather than nicotine flux, has been used to characterize the amount of nicotine emitted by different products. Nicotine yield is defined as the mass of nicotine extracted from a tobacco product by the user, per unit of consumption (e.g., milligrams of nicotine per cigarette).
Nicotine flux varies based on parameters such as mode of delivery/use, nicotine concentration, puff duration for inhaled products, duration of use for products delivered through buccal, sublingual, or transdermal methods (e.g., nicotine gum, oral pouches, and patches), product formulation, and other factors.
The formulas for nicotine flux below show how nicotine flux is also inversely proportional to the duration of product usage.
Nicotine flux doesn’t include variation in nicotine absorption rates
One limitation to the use of nicotine flux for measuring nicotine dose is that it does not translate to in vivo exposures, as it does not account for the rate of absorption of nicotine. Consequently, using products with similar nicotine flux but different modes of delivery/use (e.g., nasal sprays and oral pouches) will result in different rates of nicotine absorption and different PK profiles.
This chart illustrates that, across products available today, nicotine flux was lowest from nicotine patches and highest from nasal and mouth sprays, with consumer products like e-cigarettes, HnB products, and oral products in the middle.
As flux is defined by the dose of nicotine and duration of use, the researchers compared the contribution of each. They noted that, because different products have different usage time, the same nicotine dose could be delivered with a wide range of nicotine flux.
In fact, the researchers found almost no relationship between nicotine flux from the device and total dose of nicotine delivered to the user (based on studies that provided enough detail to assess the relationship). This suggests that nicotine flux is likely a less reliable empirical metric for assessment of inhaled nicotine delivery systems. This is because there are many factors that influence nicotine delivery in inhaled products, such as nicotine protonation, particle size distribution, differences in individual puffing behaviors, which are not accounted for in flux.
The researchers emphasized the importance of taking PK parameters into account when evaluating nicotine delivery systems. To achieve this, they proposed measuring the rate of systemic nicotine delivery. This is given by a maximum concentration of nicotine reached in the blood (Cmax) over the time it takes to reach the maximum concentration (Tmax).
They found that there is little relationship between nicotine flux from the device and Cmax/Tmax, but there is a stronger relationship between product type and Cmax/Tmax. For example, nicotine inhalers have similar nicotine flux to cigarettes or e-cigarettes, but very different Cmax/Tmax. This is due to differences in absorption rates, physiochemical properties, and deposition patterns. This suggests that Cmax/Tmax may be a better indicator of systemic exposure than nicotine flux, as it considers the variability in absorption rates of nicotine.
While the researchers found little relationship between nicotine flux and Cmax/Tmax, there was a relationship between product type and Cmax/Tmax, as can be seen in this chart.
Nicotine flux does not correlate with quitting or switching rates
The authors found almost no relationship between nicotine flux and 52-week quitting or switching success for any form of nicotine use, but there was a significant relationship between quitting and physiological measures of nicotine delivery.
Inhalation-based nicotine delivery systems which can deliver a Cmax/Tmax > 1 were found to have a higher quit success rate than products which deliver a Cmax/Tmax < 1. Products with Cmax/Tmax > 1 were also found to have a much higher rate of continued use (indicating the users continued with the lower-risk product and did not return to cigarette smoking) than products with Cmax/Tmax < 1, such as nicotine patches.
Nicotine flux doesn’t estimate abuse liability
Overall, these results indicate that nicotine flux, by itself, is a poor indicator of human exposure to nicotine and of abuse liability. Systemic nicotine exposure and the abuse liability potential of nicotine delivery systems cannot be accurately estimated by a single factor (e.g., the nicotine concentration in an e-liquid), or a combination of two parameters, such as emitted dose and duration of puffing (i.e., nicotine flux).
Instead, the research suggests that measurements of nicotine flux need to be complemented with relevant parameters, such as those based on modes of delivery/use, to yield more reliable estimations of human exposure.
The authors propose developing a preliminary set of empirical descriptions for evaluation of nicotine delivery systems based on in vitro experimentation and in silico PK predictions. For regulating abuse liability rather than using a single factor (e.g., the nicotine concentration in an e-liquid), or a combination of two parameters, such as emitted dose and duration of puffing (i.e., nicotine flux), they suggest considering the adoption of a framework that considers the interplay of factors such as device design, nicotine flux, aerosol particle size and liquid-gas distribution, inhalation topography, pH of e-liquids, nicotine PK, and aerosol deposition in airways.
