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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 (Cmax) 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.

SUBMITTER: Kovar L 

PROVIDER: S-EPMC7467963 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Kovar Lukas L   Selzer Dominik D   Britz Hannah H   Benowitz Neal N   St Helen Gideon G   Kohl Yvonne Y   Bals Robert R   Lehr Thorsten T  

Clinical pharmacokinetics 20200901 9


<h4>Background</h4>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.<h4>Objectives</h4>The aim of this study was to develop a comprehensive, whole-body, physiologically  ...[more]

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