Development of a Physiologically Based Pharmacokinetic (PBPK) Simulation Model for Nicotine

Authors: Bae SH, Kim B, Bashar M, Yi B, Rahman MA, Awuah P, Hartog M, Panarsky R, Zhang T
Publication: Drug Metab Dispos
Keywords: clinical pharmacokinetic data, electronic nicotine delivery systems (ENDS), gastroplus, nicotine, PBPK, PBPK modeling
Software: GastroPlus®

Abstract

Tobacco is a major cause of chronic diseases such as lung cancer, cardiovascular disease, and chronic obstructive pulmonary disease worldwide. Nicotine, the primary psychoactive component in tobacco, is highly addictive and while not the primary driver of such tobacco-related diseases, poses various health risks, particularly those affecting cardiovascular and pulmonary systems. While nicotine-based therapies, such as nicotine replacement products, are widely utilized in smoking cessation efforts, the pharmacokinetics and profiles of nicotine delivered through electronic nicotine delivery systems (ENDS) remain incompletely characterized and warrant continued evaluation. This study aims to develop and validate a physiologically based pharmacokinetic (PBPK) simulation model for nicotine using clinical pharmacokinetic data. The PBPK simulation model for nicotine was developed by incorporating drug-specific and system-specific parameters, and by considering the systemic absorption, distribution, metabolism, and excretion of nicotine as well as its overall pharmacokinetic behavior, on GastroPlus version 9.9. Validation of the developed PBPK model was performed by comparing predicted and observed plasma nicotine concentration-time profiles and pharmacokinetic parameters from clinical studies across different routes of administration including intravenous infusion and pulmonary inhalation. The resulting model accurately captured plasma nicotine concentrations, with predicted pharmacokinetic parameters, falling within acceptable ranges of observed values and computational average fold error values. The current model provides a practical tool to translate systemic nicotine exposure across delivery systems, support dose optimization against predefined target exposure, and quantify safety margins, thereby informing safer product design and evidence-based decisions in public-health regulatory science.

By Sung Hun Bae, Brian Kim, Mohamed Bashar,  Bofang Yi, Mohammad A. Rahman, Prince Awuah, Matthew Hartog, Rony Panarsky, Tao Zhang