Introduction
Over the past several years, the landscape of nicotine delivery products has evolved rapidly. Traditional cigarettes are now accompanied by a growing array of alternative products, including electronic nicotine delivery systems (ENDS), nicotine patches, oral nicotine pouches, and slow-release lozenges.
Nicotine pouch products such as ZYN® and On!® are increasingly positioned as reduced-harm tobacco-free alternatives. Importantly, the pharmacokinetic (PK) profiles of nicotine exposure from these products can differ from traditional combustible cigarettes. Differences in rate and extent of nicotine absorption have meaningful implications for exposure, user behavior, and abuse potential.
Importance of Substance Abuse Study Design and Integrated Pharmacokinetics
At Xyzagen, we have analyzed PK data from a number of nicotine studies across multiple product types. As new formulations continue to emerge, understanding PK across delivery methods is critical not only for product development and regulatory evaluation, but also for assessing abuse liability.
Right now, the industry uses traditional PK parameters of AUC (Area Under the Curve), Cmax, and Tmax to measure exposure over time and potentially correlate to abuse potential. However, it’s not that straight forward. Two products may have a similar Cmax but one may have a delayed Tmax, or the delayed Tmax may have a lower Cmax and similar AUC. The difference in the rate of nicotine absorption may be more important than total exposure in abuse potential, or reduction thereof.
These studies underscore the value of thoughtful study design that integrates PK characterization with abuse liability endpoints to provide a comprehensive understanding of substance use risk. This integrated approach has broad applicability across substance use disorder (SUD) programs. At Xyzagen, we combine PK expertise with specialized experience in substance abuse study design to support the development and evaluation of SUD therapeutics.
Differences in Nicotine Delivery Across Products and Routes of Administration
Electronic Nicotine Delivery Systems (ENDS), also known as e-cigarettes, e-cigs, vapes, mods, and tank systems, deliver flavored nicotine aerosol directly to the lungs, providing rapid nicotine delivery.
Nicotine pouches and lozenges contain a powder or nicotine polacrilex made of nicotine, flavorings, and other ingredients which deliver nicotine through the mucosal membranes of the mouth. Pouches and lozenges are slow-release nicotine products designed to sustain nicotine delivery without rapid spikes in concentration.
Nicotine PK: A Brief Overview
Nicotine PK is strongly influenced by the route of delivery. At Xyzagen, we have analyzed several studies that consisted of two 2-hour sessions: a standardized use and an ad libitum use session. In the standardized use session, participants consumed either a combustible cigarette or an ENDS product, where participants took a predetermined number of puffs over a 5-minute period, or used a pouch that was held between the lip and gum for 30 minutes. In the ad libitum use session the participants were allowed to use the nicotine product as they deemed appropriate.
Key PK parameters such as Cmax, Tmax, and AUC (overall exposure) were calculated due to their importance in providing insight into how the different products at different nicotine concentrations behave. These parameters dictate the rate of rise, peak concentration, and exposure profile of nicotine.
Regardless of method of delivery, Tmax occurred at the end of the consumption period during the standardized use session, approximately 5 minutes for cigarettes and ENDS and 30 minutes for pouches. Over the course of the ad libitum use session concentrations of nicotine continually trended upward regardless of method of delivery.
The amount of systemic nicotine concentration is heavily influenced by the mg dose of the ENDS cartridge or pouch, where, in some instances, nicotine concentrations were significantly higher than a combustible cigarette leading to an overall greater exposure of nicotine (AUC).
Relationship Between PK and Nicotine Abuse Potential
Differences in nicotine delivery and exposure can significantly impact user experience and abuse potential. Accordingly, PK parameters provide important insight into subjective experience and reinforcing effects.
Specifically, rapid delivery of high systemic nicotine concentrations produces a rapid increase in dopaminergic signaling within brain reward pathways. This fast onset is associated with stronger reinforcement and strengthened associations between drug effects and sensory or environmental cues. Over time, these rapid exposure profiles can strengthen behavioral rituals, cue reactivity, and craving relief.
One metric that has been proposed to characterize this relationship is the ratio between Cmax and Tmax.Cmax/Tmax>1 has been associated with greater abuse potential (faster rate of rise), whereas Cmax/Tmax<1 has been associated with low abuse potential (Kolli et al., 2024). Consistent with this framework, currently available nicotine replacement therapies exhibit Cmax/Tmax<1. However, this metric does not fully capture differences in abuse liability.
Combustible cigarettes remain the benchmark for rapid nicotine delivery, characterized by fast pulmonary absorption and high peak plasma concentrations. Many ENDS products demonstrate exposure profiles that approximate this rapid delivery pattern. In contrast, oral nicotine products such as pouches and lozenges often produce slower absorption and more prolonged exposure. While overall nicotine exposure may be comparable in some cases, the delayed Tmax and lower peak concentrations represent a fundamentally different PK profile, generally associated with lower Cmax/Tmax suggesting lower abuse potential.
However, real-world use patterns highlight the limitations of relying exclusively on this measure. For example, oral chewing tobacco exhibits a Cmax/Tmax <1 and yet, it remains widely abused. This illustrates that abuse liability cannot be fully characterized by a single exposure metric. Accordingly, it is critical to evaluate how products are used in real-world settings—how often individuals use them, how closely together doses are taken, and how nicotine exposure builds over time with repeated use. These patterns of self-administration can meaningfully influence overall exposure and abuse potential, and they cannot be fully understood from PK measurements alone. Addressing these questions requires behavioral pharmacology approaches that examine real-world use behavior alongside pharmacokinetic data.
Regulatory Considerations and Abuse Liability
As the FDA continues to evaluate nicotine-containing products, pharmacokinetics play a central role in assessing abuse potential. However, as described above, reliance on a single PK endpoint may not adequately reflect differences across product categories.
For products with fundamentally different delivery kinetics, alternative or supplemental PK endpoints as well as behavioral pharmacology endpoints may be needed to better contextualize abuse liability. These considerations are increasingly relevant as the market shifts toward novel oral and slow-release nicotine formulations.
By integrating PK analysis with product design, behavioral characterization, and regulatory strategy, developers and regulators can better understand how formulation and delivery impact real-world use.
Extending PK Principles Beyond Nicotine
Nicotine serves as a well-studied model for understanding how delivery rate and exposure influence dependence, but these principles extend beyond tobacco products. Virtually all drugs of abuse engage dopaminergic reward pathways, and their reinforcing effects are strongly influenced by the rate at which drug exposure occurs. Accordingly, PK-driven assessment of substance exposure is relevant across a wide range of compounds where abuse liability, reinforcement, and user behavior are closely tied to pharmacokinetics.
Substance Use Disorder: Nonclinical Approaches
In vivo behavioral pharmacology provides valuable insight into abuse liability of potential therapeutic agents. Several well-established preclinical behavioral assays are commonly used to characterize different dimensions of abuse potential as well as the potential for pharmacotherapies.
These assays can inform abuse liability by providing information regarding how similar the experience of a drug is to other drugs of abuse, how rewarding a drug is, and whether dependence and withdrawal symptoms can occur after prolonged use. Importantly, these assays can also evaluate candidate pharmacotherapies by determining how treatment modifies the reinforcing, discriminative, or dependence-related effects of a known drug of abuse.
When behavioral endpoints are collected alongside PK data, they enable robust PK/PD integration. This approach supports prediction of abuse liability at clinically relevant exposure levels and provides a more comprehensive framework than PK metrics alone.
Conclusion
The evolution of nicotine products highlights the importance of integrating pharmacokinetics, behavioral pharmacology, and regulatory strategy to comprehensively assess abuse liability. All of these components are critical for regulatory assessment and product development.
Contact us to learn more about our pharmacokinetic services, as well as how we can advise on nonclinical studies of abuse liability.
