Nicotine Population Pharmacokinetics in Healthy Smokers After Intravenous, Oral, Buccal and Transdermal Administration

### **Introduction**
This summary provides an overview of a comprehensive study on the population pharmacokinetics (PPK) of nicotine across various administration routes, including intravenous (IV), oral, buccal (mouth spray, chewing gum, lozenge, inhaler), and transdermal (patch) formulations. The study integrates data from multiple clinical trials to develop robust pharmacokinetic models, which are critical for optimizing nicotine replacement therapy (NRT) and understanding its exposure-response relationships. Readers will gain insights into the study design, key pharmacokinetic parameters, and the implications of these findings for NRT product development and regulatory decision-making.

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### **Key Points**
- **Study Design & Data Integration:**
- The analysis included data from 29 studies involving 930 healthy smoking volunteers, totaling 46,016 observations.
- Data were collected from IV, oral, buccal, and transdermal nicotine formulations, with separate models developed for IV and extravascular routes due to computational efficiency.
- Detectable pre-dose nicotine concentrations (from prior smoking) were modeled as a hypothetical bolus dose to account for residual nicotine.

- **Intravenous (IV) Nicotine Model:**
- A three-compartment model best described IV nicotine pharmacokinetics, with initial and terminal half-lives of 7 minutes and 4.5 hours, respectively.
- Clearance (CL) and volume of distribution (Vd) were allometrically scaled to body weight, with typical CL of 67 L/h for a 70-kg individual.

- **Oral Nicotine Model:**
- Oral bioavailability (F) was estimated at 40%, with absorption best described by a first-order process (Ka = 1.55 h⁻¹).
- Repeated dosing required a time-dependent increase in clearance (CL) or decrease in bioavailability (F) to explain observed plasma concentration profiles.

- **Buccal Nicotine Models (Mouth Spray, Gum, Lozenge, Inhaler):**
- Parallel absorption pathways were used: oromucosal absorption (F = 100%) and gastrointestinal absorption (F = 40%) after swallowing.
- The fraction swallowed (Frsw) ranged from 55% (gum) to 69% (lozenge), with chewing gum showing the fastest absorption rate (Ka = 26.5 h⁻¹).
- Repeated dosing required adjustments to CL or F to account for lower-than-expected steady-state concentrations.

- **Transdermal Nicotine Model:**
- Nicotine release from patches was modeled with parallel zero-order and first-order pathways, followed by absorption through transit compartments.
- Transdermal bioavailability (F) was estimated at 76%, with a 12% increase in CL observed upon repeated dosing.

- **Model Validation & Applications:**
- Visual predictive checks (VPCs) confirmed model reliability, though some variability was overestimated for chewing gum.
- The models were used for exposure-response analyses and simulations to optimize NRT dosing strategies.

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### **Main Message**
This study provides a rigorous, data-driven framework for understanding nicotine pharmacokinetics across multiple administration routes. The developed models offer precise estimates of key pharmacokinetic parameters, including clearance, volume of distribution, bioavailability, and absorption rates, which are essential for regulatory assessments and NRT product development. By integrating large-scale clinical data, the study enhances the scientific basis for optimizing nicotine replacement therapies, ensuring safer and more effective treatments for smoking cessation. The findings underscore the importance of tailored pharmacokinetic modeling in advancing public health strategies to combat tobacco use.

Olsson Gisleskog, P.O., Perez Ruixo, J.J., Westin, Å. et al. Nicotine Population Pharmacokinetics in Healthy Smokers After Intravenous, Oral, Buccal and Transdermal Administration. Clin Pharmacokinet 60, 541–561 (2021). https://doi.org/10.1007/s40262-020-00960-5