199: A PBPK-Driven Modeling Approach for Extrapolation of Clinical Pharmacokinetic Results for Oral Nicotine-Containing Products

Statement of Purpose: We propose a modeling framework that incorporates a clinically obtained Pharmacokinetic (PK) dataset and then extrapolate to beyond the specific use case scenarios, use duration, nicotine content in product etc., under which the study was originally designed. This approach could be potentially applied to a variety of oral nicotine-containing product categories, including pouch, gum and mouth spray.

Description of Methods & Materials: A diffusion-based buccal tissue permeation model is coupled with a recently published human nicotine PBPK model (Rostami, A.A. et al., Scientific Reports (2022) 12:1091). Two key parameters in the tissue permeation model, namely the nicotine diffusion coefficient and apparent tissue thickness are optimized by iteratively using publicly available in vivo nicotine tissue uptake and venous nicotine PK profiles. The final modeling framework uses the following input data and parameters: 1) the release rate of nicotine in the buccal cavity 2) use duration 3) nicotine transfer fraction to the gastrointestinal tract (GI) or alternatively saliva/tissue partition coefficient and 4) saliva secretion rate and swallowing frequency. The tissue permeation model predicts the nicotine uptake rate by the systemic circulation and GI transfer which are both subsequent inputs to the PBPK model. The final outcomes are time course of the mean venous nicotine plasma concentration as well as tissue concentrations for desired use case scenarios not considered in the original clinical study.

Data & Results: Using tissue uptake data publicly available only for MST category, the nicotine diffusion coefficient in buccal tissue and the apparent buccal tissue thickness were estimated at 1.2±0.3x10-5 (cm²/sec) and 1.75±0.25 mm, respectively. These two parameters were then consistently used for validation of the PBPK model across all other product categories. Nicotine PK profile as well as average product nicotine contents before and after use from a wide variety of published studies for various marketed oral nicotine product categories and brands including MST, tobacco-derived nicotine pouch, gum and mouth spray were used in PBPK model parameterization and validation.

Interpretation, Conclusion or Significance: The utility of the proposed framework is demonstrated most readily in the context of crossover studies where a PK profile is obtained for multiple nicotine strengths of a given test product. Depending on the product category and availability of use data, the model residual error varies. The mean of individual maximal plasma concentration is predicted within ~15% accuracy relative to clinical data while the time to maximum is predicted within a ~5% relative error. The proposed framework holds significant promise in reducing the clinical trials during development phase of nicotine-containing products in line with stated goal of FDA to use modeling and simulation to reduce clinical trials.

Disclosures: This study was sponsored by Altria Client Services LLC.