Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 9/2020

Open Access 01-09-2020 | Original Research Article

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

Authors: Lukas Kovar, Dominik Selzer, Hannah Britz, Neal Benowitz, Gideon St. Helen, Yvonne Kohl, Robert Bals, Thorsten Lehr

Published in: Clinical Pharmacokinetics | Issue 9/2020

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
World Health Organization. WHO report on the global tobacco epidemic, 2019. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO.
2.
World Lung Foundation. The tobacco atlas. 5. Atlanta: American Cancer Society; 2015.
3.
4.
5.
Bhatnagar A, Payne TJ, Robertson RM. Is there a role for electronic cigarettes in tobacco cessation? J Am Heart Assoc. 2019;8:e012742.PubMedPubMedCentral
6.
Benowitz NL. Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol. 2009;49:57–71.PubMedPubMedCentral
7.
Batra A, Klingler K, Landfeldt B, Friederich HM, Westin A, Danielsson T. Smoking reduction treatment with 4-mg nicotine gum: a double-blind, randomized, placebo-controlled study. Clin Pharmacol Ther. 2005;78:689–96.PubMed
8.
Hays JT, Croghan IT, Schroeder DR, Offord KP, Hurt RD, Wolter TD, et al. Over-the-counter nicotine patch therapy for smoking cessation: results from randomized, double-blind, placebo-controlled, and open label trials. Am J Public Health. 1999;89:1701–7.PubMedPubMedCentral
9.
Benowitz NL, Porchet H, Sheiner L, Jacob P. Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum. Clin Pharmacol Ther. 1988;44:23–8.PubMed
10.
Benowitz NL, Chan K, Denaro CP, Jacob P. Stable isotope method for studying transdermal drug absorption: the nicotine patch. Clin Pharmacol Ther. 1991;50:286–93.PubMed
11.
Rose JE, Mukhin AG, Lokitz SJ, Turkington TG, Herskovic J, Behm FM, et al. Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11C-nicotine. Proc Natl Acad Sci USA. 2010;107:5190–5.PubMed
12.
Xian H, Scherrer JF, Madden PAF, Lyons MJ, Tsuang M, True WR, et al. The heritability of failed smoking cessation and nicotine withdrawal in twins who smoked and attempted to quit. Nicotine Tob Res. 2003;5:245–54.PubMed
13.
Heitjan DF, Asch DA, Ray R, Rukstalis M, Patterson F, Lerman C. Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment. Pharmacogenom J. 2008;8:391–9.
14.
Lerman C, Schnoll RA, Hawk LW, Cinciripini P, George TP, Wileyto EP, et al. Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2015;3:131–8.PubMedPubMedCentral
15.
Hukkanen J, Jacob P, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev. 2005;57:79–115.PubMed
16.
Mroziewicz M, Tyndale RF. Pharmacogenetics: a tool for identifying genetic factors in drug dependence and response to treatment. Addict Sci Clin Pract. 2010;5:17–29.PubMedPubMedCentral
17.
Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis. 2003;46:91–111.PubMed
18.
Benowitz NL, Dains KM, Dempsey D, Yu L, Jacob P. Estimation of nicotine dose after low-level exposure using plasma and urine nicotine metabolites. Cancer Epidemiol Biomark Prev. 2010;19:1160–6.
19.
Zhao P, Zhang L, Grillo JA, Liu Q, Bullock JM, Moon YJ, et al. Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review. Clin Pharmacol Ther. 2011;89:259–67.PubMed
20.
Lott D, Lehr T, Dingemanse J, Krause A. Modeling tolerance development for the effect on heart rate of the selective S1P1 receptor modulator ponesimod. Clin Pharmacol Ther. 2018;103:1083–92.PubMed
21.
Tega Y, Yamazaki Y, Akanuma S, Kubo Y, Hosoya K. Impact of nicotine transport across the blood-brain barrier: carrier-mediated transport of nicotine and interaction with central nervous system drugs. Biol Pharm Bull. 2018;41:1330–6.PubMed
22.
Benowitz NL, Jacob P. Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther. 1994;56:483–93.PubMed
23.
Gubner NR, Kozar-Konieczna A, Szoltysek-Boldys I, Slodczyk-Mankowska E, Goniewicz J, Sobczak A, et al. Cessation of alcohol consumption decreases rate of nicotine metabolism in male alcohol-dependent smokers. Drug Alcohol Depend. 2016;163:157–64.PubMedPubMedCentral
24.
De Schepper PJ, Van Hecken A, Daenens P, Van Rossum JM. Kinetics of cotinine after oral and intravenous administration to man. Eur J Clin Pharmacol. 1987;31:583–8.PubMed
25.
Benowitz NL, Jacob P. Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers. Clin Pharmacol Ther. 1993;53:316–23.PubMed
26.
Simon DL, Iglauer A. The acute effect of chewing tobacco and smoking in habitual users. Ann N Y Acad Sci. 1960;90:119–32.
27.
Porchet HC, Benowitz NL, Sheiner LB. Pharmacodynamic model of tolerance: application to nicotine. J Pharmacol Exp Ther. 1988;244:231–6.PubMed
28.
Morjaria Y, Irwin WJ, Barnett PX, Chan RS, Conway BR. In vitro release of nicotine from chewing gum formulations. Dissolution Technol. 2004;11:12–5.
29.
Houseman TH. Studies of cigarette smoke transfer using radioisotopically labelled tobacco constituents part II: the transference of radioisotopically labelled nicotine to cigarette smoke. Beitrage zur Tab Int Contrib to Tob Res. 1973;7:142–7.
30.
Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, et al. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006;34:D668–72.PubMed
31.
Nielsen HM, Rassing MR. Nicotine permeability across the buccal TR146 cell culture model and porcine buccal mucosa in vitro: effect of pH and concentration. Eur J Pharm Sci. 2002;16:151–7.PubMed
32.
Alharbi O, Xu Y, Goodacre R. Simultaneous multiplexed quantification of nicotine and its metabolites using surface enhanced Raman scattering. Analyst. 2014;139:4820–7.PubMed
33.
Zissimos AM, Abraham MH, Barker MC, Box KJ, Tam KY. Calculation of Abraham descriptors from solvent-water partition coefficients in four different systems; evaluation of different methods of calculation. J Chem Soc Perkin Trans. 2002;2:470–7.
34.
Svensson CK. Clinical pharmacokinetics of nicotine. Clin Pharmacokinet. 1987;12:30–40.PubMed
35.
Benowitz NL, Kuyt F, Jacob P, Jones RT, Osman AL. Cotinine disposition and effects. Clin Pharmacol Ther. 1983;34:604–11.PubMed
36.
Yamazaki H, Inoue K, Hashimoto M, Shimada T. Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol. 1999;73:65–70.PubMed
37.
Fukami T, Nakajima M, Yoshida R, Tsuchiya Y, Fujiki Y, Katoh M, et al. A novel polymorphism of human CYP2A6 gene CYP2A6*17 has an amino acid substitution (V365M) that decreases enzymatic activity in vitro and in vivo. Clin Pharmacol Ther. 2004;76:519–27.PubMed
38.
Hosono H, Kumondai M, Maekawa M, Yamaguchi H, Mano N, Oda A, et al. Functional characterization of 34 CYP2A6 allelic variants by assessment of nicotine C-oxidation and coumarin 7-hydroxylation activities. Drug Metab Dispos. 2017;45:279–85.PubMed
39.
Murphy SE, Raulinaitis V, Brown KM. Nicotine 5′-oxidation and methyl oxidation by P450 2A enzymes. Drug Metab Dispos. 2005;33:1166–73.PubMed
40.
Xu C, Rao YS, Xu B, Hoffmann E, Jones J, Sellers EM, et al. An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles. Biochem Biophys Res Commun. 2002;290:318–24.PubMed
41.
Dicke KE, Skrlin SM, Murphy SE. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone metabolism by cytochrome P450 2B6. Drug Metab Dispos. 2005;33:1760–4.PubMed
42.
Rodgers T, Rowland M. Mechanistic approaches to volume of distribution predictions: understanding the processes. Pharm Res. 2007;24:918–33.PubMed
43.
Rodgers T, Leahy D, Rowland M. Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci. 2005;94:1259–76.PubMed
44.
Rodgers T, Rowland M. Physiologically-based pharmacokinetic modeling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95:1238–57.PubMed
45.
Hindmarsh AC, Reynolds DR, Serban R, Woodward CS, Gardner DJ, Cohen SD, et al. Open systems pharmacology suite manual, version 7.4.; 2018.
46.
Armitage AK, Dollery CT, George CF, Houseman TH, Lewis PJ, Turner DM. Absorption and metabolism of nicotine from cigarettes. Br Med J. 1975;4:313–6.PubMedPubMedCentral
47.
Hammond D, Fong GT, Cummings KM, O’Connor RJ, Giovino GA, McNeill A. Cigarette yields and human exposure: a comparison of alternative testing regimens. Cancer Epidemiol Biomark Prev. 2006;15:1495–501.
48.
Benowitz NL. Compensatory smoking of low-yield cigarettes. In: Burns DM, Benowitz NL, Amacher RH (eds) Smok Tob Control Monogr No 13. 2001: p. 39–64.
49.
Robinson DE, Balter NJ, Schwartz SL. A physiologically based pharmacokinetic model for nicotine and cotinine in man. J Pharmacokinet Biopharm. 1992;20:591–609.PubMed
50.
Plowchalk DR, Andersen ME, DeBethizy JD. A physiologically based pharmacokinetic model for nicotine disposition in the Sprague-Dawley rat. Toxicol Appl Pharmacol. 1992;116:177–88.PubMed
51.
Yamazaki H, Horiuchi K, Takano R, Nagano T, Shimizu M, Kitajima M, et al. Human blood concentrations of cotinine, a biomonitoring marker for tobacco smoke, extrapolated from nicotine metabolism in rats and humans and physiologically based pharmacokinetic modeling. Int J Environ Res Public Health. 2010;7:3406–21.PubMedPubMedCentral
52.
Teeguarden JG, Housand CJ, Smith JN, Hinderliter PM, Gunawan R, Timchalk CA. A multi-route model of nicotine-cotinine pharmacokinetics, pharmacodynamics and brain nicotinic acetylcholine receptor binding in humans. Regul Toxicol Pharmacol. 2013;65:12–28.PubMed
53.
Gajewska M, Worth A, Urani C, Briesen H, Schramm K-W. The acute effects of daily nicotine intake on heart rate—a toxicokinetic and toxicodynamic modelling study. Regul Toxicol Pharmacol. 2014;70:312–24.PubMed
54.
Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics. 2007;8:743–59.PubMed
55.
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Annu Rev Med. 2006;57:119–37.PubMed
56.
Kovar L, Schmidt S. Derendorf H. Maßgeschneidert: Die Pharmakogenetik ebnet den Weg für erfolgreiche individualisierte Interventionen. DAZ; 2018. p. 3000–4.
57.
Cullen KA, Ambrose BK, Gentzke AS, Apelberg BJ, Jamal A, King BA. Use of electronic cigarettes and any tobacco product among middle and high school students: United States, 2011–2018. Am J Public Health. 2018;67:1277.
58.
Meyer M, Schneckener S, Ludewig B, Kuepfer L, Lippert J. Using expression data for quantification of active processes in PBPK modeling. Drug Metab Dispos. 2012;40:892–901.PubMed
59.
Schorp MK. Summary of literature data on smoking topography. In: Pick W, Houlgate P, Schorp MK, et al. (eds) A Rev Hum Smok Behav Recomm a New ISO Stand Mach Smok Cigarettes; Rep Ad Hoc WG9 Smok R Beirut, Lebanon Am Univ Beirut. 2005: p. 28–50.
60.
Ross KC, Dempsey DA, St. Helen G, Delucchi K, Benowitz NL. The influence of puff characteristics, nicotine dependence, and rate of nicotine metabolism on daily nicotine exposure in African American smokers. Cancer Epidemiol Biomark Prev. 2016;25:936–43.
61.
St Helen G, Ross KC, Dempsey DA, Havel CM, Jacob P, Benowitz NL. Nicotine delivery and vaping behavior during ad libitum E-cigarette access. Tob Regul Sci. 2016;2:363–76.PubMedPubMedCentral
62.
Bannon YB, Corish J, Corrigan OI, Devane JG, Kavanagh M, Mulligan S. Transdermal delivery of nicotine in normal human volunteers: a single dose and multiple dose study. Eur J Clin Pharmacol. 1989;37:285–90.PubMed
63.
Vandewalle G, Middleton B, Rajaratnam SMW, Stone BM, Thorleifsdottir B, Arendt J, et al. Robust circadian rhythm in heart rate and its variability: influence of exogenous melatonin and photoperiod. J Sleep Res. 2007;16:148–55.PubMed
64.
Ambre JJ, Belknap SM, Nelson J, Ruo TI, Shin SG, Atkinson AJ. Acute tolerance to cocaine in humans. Clin Pharmacol Ther. 1988;44:1–8.PubMed
65.
Haass M, Kübler W. Nicotine and sympathetic neurotransmission. Cardiovasc Drugs Ther. 1996;10:657–65.
66.
Stéphan-Blanchard E, Bach V, Telliez F, Chardon K. Perinatal nicotine/smoking exposure and carotid chemoreceptors during development. Respir Physiol Neurobiol. 2013;185:110–9.PubMed
67.
Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol. 1997;29:1422–31.PubMed
68.
Fagerström KO, Schneider NG, Lunell E. Effectiveness of nicotine patch and nicotine gum as individual versus combined treatments for tobacco withdrawal symptoms. Psychopharmacology. 1993;111:271–7.PubMed
69.
Stein PK, Rottman JN, Kleiger RE. Effect of 21 mg transdermal nicotine patches and smoking cessation on heart rate variability. Am J Cardiol. 1996;77:701–5.PubMed
70.
Mendelson JH, Goletiani N, Sholar MB, Siegel AJ, Mello NK. Effects of smoking successive low- and high-nicotine cigarettes on hypothalamic-pituitary-adrenal axis hormones and mood in men. Neuropsychopharmacology. 2008;33:749–60.PubMed
71.
Benowitz NL, Kuyt F, Jacob P. Circadian blood nicotine concentrations during cigarette smoking. Clin Pharmacol Ther. 1982;32:758–64.PubMed
72.
Feyerabend C, Ings RM, Russel MA. Nicotine pharmacokinetics and its application to intake from smoking. Br J Clin Pharmacol. 1985;19:239–47.PubMedPubMedCentral
73.
74.
Zevin S, Jacob P, Benowitz N. Cotinine effects on nicotine metabolism. Clin Pharmacol Ther. 1997;61:649–54.PubMed
75.
Curvall M, Elwin CE, Kazemi-Vala E, Warholm C, Enzell CR. The pharmacokinetics of cotinine in plasma and saliva from non-smoking healthy volunteers. Eur J Clin Pharmacol. 1990;38:281–7.PubMed
76.
Benowitz NL, Jacob P, Fong I, Gupta S. Nicotine metabolic profile in man: comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther. 1994;268:296–303.PubMed
77.
Du D. A single-dose, crossover-design bioequivalence study comparing two nicotine gum formulations in healthy subjects. Adv Ther. 2018;35:1169–80.PubMedPubMedCentral
78.
Dautzenberg B, Nides M, Kienzler J-L, Callens A. Pharmacokinetics, safety and efficacy from randomized controlled trials of 1 and 2 mg nicotine bitartrate lozenges (Nicotinell). BMC Clin Pharmacol. 2007;7:11.PubMedPubMedCentral
79.
Gupta SK, Benowitz NL, Jacob P, Rolf CN, Gorsline J. Bioavailability and absorption kinetics of nicotine following application of a transdermal system. Br J Clin Pharmacol. 1993;36:221–7.PubMedPubMedCentral
80.
Gilbert DG, Robinson JH, Chamberlin CL, Spielberger CD. Effects of smoking/nicotine on anxiety, heart rate, and lateralization of EEG during a stressful movie. Psychophysiology. 1989;26:311–20.PubMed
81.
St Helen G, Havel C, Dempsey DA, Jacob P, Benowitz NL. Nicotine delivery, retention and pharmacokinetics from various electronic cigarettes. Addiction. 2016;111:535–44.PubMed
Metadata
Title
Comprehensive Parent–Metabolite PBPK/PD Modeling Insights into Nicotine Replacement Therapy Strategies
Authors
Lukas Kovar
Dominik Selzer
Hannah Britz
Neal Benowitz
Gideon St. Helen
Yvonne Kohl
Robert Bals
Thorsten Lehr
Publication date
01-09-2020
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 9/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-020-00880-4

Other articles of this Issue 9/2020

Clinical Pharmacokinetics 9/2020 Go to the issue

Review Article

Preclinical Pharmacokinetic/Pharmacodynamic Studies and Clinical Trials in the Drug Development Process of EMA-Approved Antibacterial Agents: A Review

Original Research Article

Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 1: Clinical Studies in Healthy Men and Patients with Castration-Resistant Prostate Cancer

EDITORIAL

Roger W. Jelliffe, M.D. (1929–2020)

Original Research Article

Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects

Review Article

Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors: An Updated Review

Current Opinion

Pharmacokinetics and Generic Drug Switching: A Regulator’s View