Nicotine Tob Res 2003;5:181-7. George TP, Vessicchio JC Sacco KA, et al. A placebo-controlled trial of bupropion combined with nicotine patch for smoking cessation in schizophrenia.
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Cigarette smoking causes serious chronic diseases, including lung cancer, chronic obstructive pulmonary disease, cardiovascular disease and stroke [1, 2]. To reduce the morbidity and mortality attributable to smoking, tobacco control measures have been implemented in many countries. While smoking rates have been successfully reduced, they remain relatively high, and the World Health Organization estimates that there will be over a billion smokers by 2025 [3].
To complement tobacco control, approaches to tobacco harm reduction have been introduced with the development of alternative nicotine delivery systems, including the Tobacco Heating System 2.2 (THS 2.2). By heating instead of burning tobacco, THS avoids or reduces the formation of many toxic combustion products. Clinical studies have shown favorable biological effects in smokers who switched from cigarette to different non-combusted products [4, 5, 6]. While this makes risk reduction at the individual level possible, a population health benefit additionally depends on smokers actually switching from cigarettes to THS. A key requisite of THS or any other alternative nicotine delivery system thus is that it satisfies smokers and in particular furnishes a nicotine uptake profile similar to cigarettes [7], making pharmacokinetic assessment essential.
Clinical trials comparing the bioavailability of nicotine with THS 2.2, either mentholated or not, with various tobacco products (regular or mentholated CC, nicotine nasal spray (NNS), or mentholated nicotine gum), have been conducted in healthy adult smokers, in various populations. Data from 8 trials allowed for characterizing nicotine pharmacokinetics and sources of variability in a retrospective population analysis.
While designing single use cross-over trials, the duration of smoking abstinence prior to first product use and the duration of the washout period assumed that plasma nicotine terminal half-life (t1/2, z) was approximately 2 h [8, 9]. However, in our clinical trials pre-dose nicotine plasma concentrations were often measurable in both study periods [7], resulting in carry-over. The reasons underlying the discrepancy between the literature-based half-life on the one hand and our findings of pre-dose and carry-over levels on the other hand might include: (1) high assay sensitivity in our studies; (2) prior background exposure; (3) insufficient duration of abstinence or washout periods; or (4) the nicotine half-life being longer than reported in the literature.
The objectives of this analysis were to (1) develop a population pharmacokinetic model describing plasma concentration–time profiles of nicotine based on single product use study data, (2) assess sources of variability in nicotine pharmacokinetic parameters, (3) estimate plasma exposure to nicotine, distinguishing between exposure due to product use and background exposure, and (4) assess the predictive performance of the nicotine population pharmacokinetic model in data from ad libitum use studies.