WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The pharmacokinetics of carboxyhaemoglobin have been reported previously, primarily with regard to poisoning and toxicity.• Most of these reports have involved noncompartmental analysis of data obtained where the actual dose of carbon monoxide was not known. WHAT THIS STUDY ADDS• This study presents a comprehensive population pharmacokinetic model for carboxyhaemoglobin in adult cigarette smokers.• Since carboxyhaemoglobin is a marker of cigarette smoke exposure, model-based evaluations can be used for simulation and other evaluations of the kinetics of this agent. AIMSTo develop a population-based model to describe and predict the pharmacokinetics of carboxyhaemoglobin (COHb) in adult smokers. METHODSData from smokers of different conventional cigarettes (CC) in three open-label, randomized studies were analysed using NONMEM (version V, Level 1.1). COHb concentrations were determined at baseline for two cigarettes [Federal Trade Commission (FTC) tar 11 mg; CC1, or FTC tar 6 mg; CC2]. On day 1, subjects were randomized to continue smoking their original cigarettes, switch to a different cigarette (FTC tar 1 mg; CC3), or stop smoking. COHb concentrations were measured at baseline and on days 3 and 8 after randomization. Each cigarette was treated as a unit dose assuming a linear relationship between the number of cigarettes smoked and measured COHb percent saturation. Model building used standard methods. Model performance was evaluated using nonparametric bootstrapping and predictive checks. RESULTSThe data were described by a two-compartment model with zero-order input and first-order elimination with endogenous COHb. Model parameters included elimination rate constant (k10), central volume of distribution (Vc/F), rate constants between central and peripheral compartments (k12 and k21), baseline COHb concentrations (c0), and relative fraction of carbon monoxide absorbed (F1). The median (range) COHb half-lives were 1.6 h (0.680-2.76) and 30.9 h (7.13-367) (a and b phases, respectively). F1 increased with increasing cigarette tar content and age, whereas k12 increased with ideal body weight. CONCLUSIONA robust model was developed to predict COHb concentrations in adult smokers and to determine optimum COHb sampling times in future studies.

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B46 Introduction It has been recently suggested in literature that adult smokers may be considering smokeless tobacco products (STP) as an alternative to smoking. While there are several STP available commercially, there is significant interest in tobacco pouch products (referred to as Snus), similar to those available in Sweden. There are few studies that have systematically investigated the changes in exposure when adult smokers use such products. Therefore, this study was conducted with the objective to evaluate the change in exposure in adult smokers who use unidentified Marlboro Snus (MS). Methods: A randomized, controlled, open-label study was conducted in which 120 adult smokers were randomized into one of the groups; CS - subjects (n=30) continue smoking their own brand, DU - subjects (n=60) reduced their normal daily cigarette consumption by ≥ 50% and were allowed to use MS (~0.3 g tobacco in a pouch, ~4 mg nicotine in tobacco) in test market in June 2007, ExclSn- subjects (n=15) stopped smoking their cigarettes but were allowed to use MS, StopTob- Subjects (n=15) were not allowed to use any tobacco products for the entire duration of the eight day study. Biomarkers of exposure measured at Baseline (Days -2 and -1) and Days 7 and 8 were 24 hr urinary excretion of the N-nitrosamines (total NNAL and total NNN), nicotine (estimated as nicotine equivalents - NE), o-toluidine (OT), 2-aminonaphthalene (2-AN), 4-aminobiphenyl (4-ABP), S-phenyl mercapturic acid (S-PMA), 3-hydroxy benzo[a]pyrene (3-OH BaP) and urine mutagenicity; plasma nicotine, cotinine, trans-3’hydroxycotinine, and blood carboxyhemoglobin (COHb) were also measured at various time points. Results Statistically significant (p < 0.05) reductions in post-baseline 24-hr urinary levels of NNAL, NNN, NE, OT, 2-AN, 4-ABP, S-PMA, 3-OH BaP, urine mutagenicity and COHb were observed in adult smokers in the DU group compared to CS. After correcting for the residual effect, using the biomarker levels in the StopTob Group, a proportionate ~50% reduction in most of the biomarkers (except for urinary NE ~36%, OT ~24%, and COHb ~ 29%) were observed. The overall average MS consumption in the DU group was 2.6 pouches/day with a residence time of 54.3 minutes. Adult smokers in the ExclSn group manifested an even larger reduction in all the urinary and blood biomarkers of exposure when compared to those in the DU group. These reductions in the ExclSn Group were similar (p>0.05) to that observed for the StopTob Group for all the biomarkers of exposure except urinary NNN (-81%), NNAL (-62%), and nicotine equivalents(-71%). MS consumption was 4 pouches/day and the average residence time was 49.4 minutes in the ExclSn group. Conclusion It can be concluded from this study that there is minimal contribution to exposure from MS in the dual usage group when adult smokers reduce the number of cigarettes by > 50% and chose to use MS under the consumption patterns observed in this study. The adult smokers sustained a substantial reduction in exposure when exclusively using MS. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B46.