A Randomized Control Study in Healthy Adult Smokers to Assess Reduced Exposure to Selected Cigarette Smoke Constituents in Switching to the Novel Heated Tobacco Product DT3.0a.

This was a randomized, controlled, open-label, confinement study to assess change in exposure to selected cigarette smoke constituents in healthy adult cigarette smokers who switched to using a novel heated tobacco product (direct heating tobacco system, platform 3, generation 3, version a [DT3.0a]). Sixty nonmenthol cigarette smokers were randomized into 1 of the 4 study groups in which subjects switched to a nonmenthol type of tobacco stick used with DT3.0a, switched to a nonmenthol tobacco stick used with an in-market heated tobacco product device (THS), continued to smoke nonmenthol cigarettes, or stopped smoking. Furthermore, 30 menthol cigarette smokers were randomized into 1 of the 2 study groups in which subjects switched to a menthol tobacco stick used with DT3.0a (mDT3.0a) or continued to smoke menthol cigarettes. Fifteen biomarkers of exposure to selected harmful and potentially harmful constituents (HPHCs) were measured during the 5-day exposure period, followed by assessment of nicotine pharmacokinetics with the assigned product. Results indicated that switching to DT3.0a, THS, and mDT3.0a showed significant exposure reductions in most of the selected HPHCs as compared to continuing smoking cigarettes, with reductions being similar in magnitude to reductions observed with smoking cessation. For DT3.0a and mDT3.0a, nicotine pharmacokinetic parameters were not remarkably different from those obtained for cigarettes and the THS except that a longer time to maximum concentration was obtained following use of the mDT3.0a. In conclusion, switching from smoking cigarettes to DT3.0a or THS use reduced exposure to most of the selected HPHCs, and no remarkable differences were observed for the measurements obtained from different flavors of DT3.0a stick.

Assessment of the exposure to selected smoke constituents in adult smokers using in-market heated tobacco products: a randomized, controlled study.

The objectives of this clinical study were to demonstrate a reduction in exposure to selected harmful and potentially harmful constituents (HPHCs) in Japanese healthy adult smokers who switched to four in-market heated tobacco products. Eighty-nine smokers were randomly assigned for five days to one of six study groups: four groups who switched to one of the commercially available heated tobacco products; a group who continued to smoke their own brand of combustible cigarettes (CC); or a group who stopped smoking (SS). Fifteen biomarkers of exposure (BoE) to 14 HPHCs and pyrene were measured at baseline, Day 3 and Day 5 in 24 h urine and breath, under clinical confinement. Product consumption, nicotine uptake and subjective effects were also measured before and after product switching. On Day 5, significant reductions in most BoE relative to the CC group were observed after switching to heated tobacco products. No changes in BoE were observed between baseline and Day 5 in the CC group. Significantly, the magnitude of the reduction in exposure to most of the selected HPHCs observed in the heated tobacco product groups was close to that observed in the SS group.

A study to investigate changes in the levels of biomarkers of exposure to selected cigarette smoke constituents in Japanese adult male smokers who switched to a non-combustion inhaler type of tobacco product.

In a clinical study, changes in 14 biomarkers of exposures (BOEs) from 10 tobacco smoke constituents and mutagens detected by the urine mutagenicity test were investigated using a non-combustion inhaler type of tobacco product (NCIT) by switching from a conventional cigarette. This study was conducted in 80 Japanese healthy adult males with a 4-week residential, controlled, open-label, parallel group design. After randomization, 40 smokers used NCIT with approximately 750 aspirations, other 20 smokers smoked approximately 20 pieces of an assigned 1-mg ISO tar conventional cigarette (CC1) every day. Twenty non-smokers (NS) did not use any tobacco product. Under this study condition, switching from cigarette to NCIT showed significant reduction in all BOEs measured. On day 29, the levels of these BOEs were almost the same as those in the NS group, except BOEs of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). This suggested that the exposure to 8 constituents and mutagens in the NCIT group was similar to that in the NS group, while the exposure to nicotine was higher. Although the precise exposure level to NNK was not estimated because of the long half-life of its BOE, it would be substantially lower in the NCIT group than in the CC1 group.

Exposure evaluation of adult male Japanese smokers switched to a heated cigarette in a controlled clinical setting.

The objective of this clinical study was to investigate changes in levels of biomarkers of exposure (BOEs) in healthy Japanese male smokers who switched to a prototype heated cigarette (HC). This was a controlled, semi-randomized, open-label, residential study conducted in Japan. A total of 70 healthy Japanese male smokers were enrolled. Following enrollment, subjects smoked their usual brand of cigarette for 2days and were subsequently randomized either to an HC group or a 10mg tar conventional cigarette (CC10) group for four consecutive weeks. Levels of BOEs for ten selected cigarette smoke constituents (nicotine, carbon monoxide (CO), benzene, 1,3-butadiene, acrolein, hydrogen cyanide, crotonaldehyde, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK], pyrene, 4-aminobiphenyl), and urine mutagenicity were measured at several time points during the study period. At the end of the study period, except for blood carboxyhemoglobin, levels of BOEs for the other nine constituents and urine mutagenicity were significantly lower in the HC group compared to the CC10 group. These results suggest that exposure to most cigarette smoke constituents, except CO, can be reduced by switching from CC10 to HC.

Good relationship between saliva cotinine kinetics and plasma cotinine kinetics after smoking one cigarette.

This study investigated the relationship between plasma and saliva cotinine kinetics after smoking one cigarette and the relationship between cotinine kinetics and estimated nicotine intake, which was calculated as mouth level exposure (MLE) of nicotine, from smoking two test cigarettes with different nicotine yields. This study was conducted in 16 healthy adult Japanese smokers, who did not have null nor reduced-activity alleles of CYP2A6, with a quasi-randomized crossover design of smoking a low-tar cigarette or a high-tar cigarette. Saliva cotinine showed similar concentration profiles to plasma cotinine, and all of the calculated pharmacokinetic parameters of cotinine showed the same values in plasma and saliva. The Cmax and AUC of cotinine showed almost the same dose-responsiveness to the estimated MLE of nicotine between plasma and saliva, but the tmax and t1/2 of cotinine were not affected by the estimated MLE of nicotine in either plasma or saliva. The results show that saliva cotinine kinetics reflects plasma cotinine kinetics, and measurement of saliva cotinine concentration gives the same information as plasma cotinine on the nicotine intake. Thus, saliva cotinine would be a good and less-invasive exposure marker of cigarette smoke, reflecting the plasma cotinine concentration and kinetics.

Pharmacokinetic analysis of nicotine when using non-combustion inhaler type of tobacco product in Japanese adult male smokers.

In a clinical study, the pharmacokinetics of nicotine were investigated using the prototype of a non-combustion inhaler type of tobacco product (PNCIT) with comparison to a 1mg tar conventional cigarette (CC). The study was conducted in 12 healthy adult Japanese male smokers with an open-label non-randomized design to make an intra-subject comparison of the use or smoking of these products. Subjects used a single piece of PNCIT with 80 aspirations or smoked a CC with 10 puffs every hour, for a total of 12 PNCITs or CCs on each study day. Under this study regimen, the steady state plasma nicotine concentration was not significantly different between the test tobacco products. The time to reach the maximum plasma nicotine concentration was longer for PNCIT compared to CC, suggesting that nicotine delivered from PNCIT was absorbed primarily in the upper airway, not in the pulmonary sites as cigarette smoking. The relative bioavailability of nicotine for PNCIT compared to CC was 0.92 ± 0.32, indicating similar nicotine bioavailability for both forms. The difference in the elimination half-lives between the test products was not significant, suggesting that the elimination of nicotine from blood is not affected significantly by the difference in the nicotine absorption sites.