Comprehensive Parent–Metabolite PBPK/PD Modeling Insights into Nicotine Replacement Therapy Strategies

Abstract

Background Nicotine, the pharmacologically active substance in both tobacco and many electronic cigarette (e-cigarette) liquids, is responsible for the addiction that sustains cigarette smoking. With 8 million deaths worldwide annually, smoking remains one of the major causes of disability and premature death. However, nicotine also plays an important role in smoking cessation strategies. Objectives The aim of this study was to develop a comprehensive, whole-body, physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) model of nicotine and its major metabolite cotinine, covering various routes of nicotine administration, and to simulate nicotine brain tissue concentrations after the use of combustible cigarettes, e-cigarettes, nicotine gums, and nicotine patches. Methods A parent-metabolite, PBPK/PD model of nicotine for a non-smoking and a smoking population was developed using 91 plasma and brain tissue concentration-time profiles and 11 heart rate profiles. Among others, cytochrome P450 (CYP) 2A6 and 2B6 enzymes were implemented, including kinetics for CYP2A6 poor metabolizers. Results The model is able to precisely describe and predict both nicotine plasma and brain tissue concentrations, cotinine plasma concentrations, and heart rate profiles. 100% of the predicted area under the concentration-time curve (AUC) and maximum concentration (C max) values meet the twofold acceptance criterion with overall geometric mean fold errors of 1.12 and 1.15, respectively. The administration of combustible cigarettes, e-cigarettes, nicotine patches, and nicotine gums was successfully implemented in the model and used to identify differences in steady-state nicotine brain tissue concentration patterns. Conclusions Our PBPK/PD model may be helpful in further investigations of nicotine dependence and smoking cessation strategies. As the model represents the first nicotine PBPK/PD model predicting nicotine concentration and heart rate profiles after the use of e-cigarettes, it could also contribute to a better understanding of the recent increase in youth e-cigarette use.

Physiologically Based Pharmacokinetic Modelling for Nicotine and Cotinine Clearance in Pregnant Women

“…An early PBPK model developed for adult men, not pregnant women, used data from intravenous nicotine infusion experiments to find pharmacokinetic parameters ( Robinson et al, 1992 ). Recent PBPK models for nicotine were also reported, e.g., by Kovar et al (2020) to simulate nicotine brain tissue concentrations after the use of combustible cigarettes, e-cigarettes, nicotine gums, and nicotine patches, and by Saylor and Zhang (2016) where antibody affinity to nicotine was considered in a PBPK model for nicotine disposition in the brains of rats and humans. Specific to p-PBPK model, Gaohua et al (2012) used it to investigate the PK profiles of three compounds (caffeine, metoprolol and midazolam) in response to the gestational related activities of three cytochrome P450 enzymes.…”

Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients

“…As a sustained-release formulation, transdermal patches can potentially reduce plasma concentration fluctuations, ADRs such as constipation and the risk for non-adherence [ 70 ]. Based on the good model performance, the fentanyl PBPK models developed in this analysis could be augmented to mechanistically model and simulate the delivery of fentanyl via more complex formulations, such as transdermal or sublingual vehicles [ 72 ].…”

Predicting Regional Respiratory Tissue and Systemic Concentrations of Orally Inhaled Drugs through a Novel PBPK Model

“…To develop OI-PBPK model for these drugs, the reported morphine (Emoto et al, 2018) and nicotine (Kovar et al, 2020) PBPK models following their intravenous (IV) administration (see Tables S6 and S7 for drug-dependent parameters) were adopted. Then, validation of the OI-PBPK model for morphine and nicotine was conducted as follows.…”