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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Philip Morris USA, Richmond, Virginia.
Address for correspondence: Hans J. Roethig, MD, PhD, FCP, FFPM, Philip Morris USA Inc, Research Center, 4201 Commerce Road, Richmond, VA 23234; e-mail: hans-juergen.roethig{at}pmusa.com.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Biomarkers • exposure • cardiovascular risk factors • EHCSS • potential reduced-exposure tobacco product
11,14,15), and platelet activation (urine 11-dehydrothromboxane B211,15); increased red blood cell mass (hemoglobin)16; and abnormal lipoprotein metabolism (decreased high-density lipoprotein [HDL] cholesterol8,7,11,12). Reducing exposure to toxic cigarette smoke constituents by using a potential reduced-exposure product (PREP) instead of conventional cigarettes could potentially lower health risks in adult smokers.17 We have previously shown that adult cigarette smokers who switched from an 11-mg tar (Federal Trade Commission [FTC]) conventional cigarette to a second-generation electrically heated cigarette smoking system (EHCSS) for 8 days in a controlled, confined, clinical setting had 43% to 85% reductions in biomarkers of exposure to smoke constituents compared with those who continued to smoke conventional cigarettes.18 The EHCSS consists of a battery-powered heater the size of a cigarette pack and a special cigarette that is inserted into the heater. One of 8 blades in the heater is activated during puffing for a total of 8 puffs per cigarette. The lower pyrolysis/combustion temperature results in substantial reductions of smoke constituents compared with conventional cigarettes.19,20
The purpose of this study was to assess changes in exposure to selected cigarette smoke constituents in adult smokers who switched to this second-generation EHCSS for 12 months in their normal life setting and to investigate whether any observed changes in exposure were accompanied by changes in cardiovascular risk factors.
Urine biomarkers of exposure for this study included nicotine and 5 major metabolites (nicotine-glucuronide, cotinine and its glucuronide, trans-3'-hydroxycotinine and its glucuronide), expressed as nicotine equivalents that reflects about 90% of the nicotine absorbed21; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (total NNAL), metabolites of the particulate-phase smoke constituent NNK, a tobacco-specific nitrosamine; 3-hydroxypropylmercapturic acid (3-HPMA), a metabolite of acrolein; 1-hydroxypyrene (1-OHP) and its glucuronide and sulfate (total 1-OHP), metabolites of pyrene, a polycyclic aromatic hydrocarbon; and urine mutagenicity. Blood biomarkers of exposure included plasma cotinine, carboxyhemoglobin (COHb), a biomarker for carbon monoxide, and 4-aminobiphenyl hemoglobin (4-ABP Hb) adducts, reflecting aromatic amines.
The cardiovascular risk factors evaluated were hemoglobin (Hb), hematocrit (Hct), red blood cell count (RBC), white blood cell count (WBC), fibrinogen, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hs-CRP), bilirubin, von Willebrand Factor, 11-dehydrothromboxane B2 (11-DHT-B2), 8-epi-prostaglandin F2 (8-epi-PGF2), and microalbumin.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Exclusion criteria included clinically significant renal, hepatic, metabolic, cardiac, and pulmonary disease; illicit drug use; use of nicotine-containing products other than manufactured cigarettes; and unwillingness to use the EHCSS exclusively. Women were excluded if they were pregnant, lactating, or intended to get pregnant during the study period. Stable doses of concomitant medications (eg, hormonal contraceptives) were permitted during the study.
Study Design and Conduct
This study used a randomized, controlled, forced-switching, open-label, parallel design conducted at 2 clinical study centers. After passing screening, subjects had 3 baseline urine and blood biomarker determinations over a 2-week interval in a controlled, confined clinical setting. Eligible adult smokers were then randomly switched to the EHCSS or to a 6-mg tar (FTC) conventional cigarette (CC) in a 2:1 ratio. Study group randomization was stratified by gender, study site, and self-reported daily cigarette consumption (10-25 and 26-40 cigarettes per day). Sample size was set arbitrarily at 80 for the EHCSS group and 40 for the CC control group to have at least 30 evaluable subjects in each group at the end of the study.
After randomization, each subject returned to the clinic at 2 weeks and at 1, 2, 3, 4, 5, 6, 9, and 12 months for blood and 24-hour urine sampling (07:00 to 07:00) in a controlled, confined clinic setting. Urine aliquots for biomarker analysis were stored at -20°C or -70°C, as appropriate for each biomarker. Subjects were queried at each visit about nonstudy cigarette consumption in addition to the assigned study product since their last visit. Subjects randomized to the EHCSS group also provided spot urine samples every 2 weeks for analysis of total NNAL as a compliance check for exclusive use of the EHCSS. If NNAL values were above 400 ng/g creatinine, subjects were counseled about the importance of compliance with the study requirements during the next study visit. Subjects who were more than 2 times above the limit were removed from the study.
Blood samples were obtained during each scheduled clinic visit at 07:00 for all blood biomarkers; at 11:00, 15:00, 19:00, and 23:00 for COHb; and at 19:00 for plasma cotinine.
Each subject self-recorded cigarette consumption on a diary card during the 24-hour investigational visits. Subjects were permitted to smoke their assigned study cigarettes ad libitum. Subjects were never required to smoke by the study staff and were allowed to reduce their daily cigarette consumption or to quit smoking at any time during the study.
The study was approved by a local institutional review board and conducted by MDS Pharma Services in Lincoln, Nebraska, and Phoenix, Arizona, in accordance with Good Clinical Practice22 and principles of the Declaration of Helsinki (2000).23
Test Products
Tar, nicotine, and carbon monoxide (CO) deliveries in mainstream smoke of the 2 cigarette products used in this study were determined from smoking machines operated under FTC conditions (Table I).
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Study cigarettes were provided to the subjects and dispensed at 2- to 8-week intervals throughout the 12 months based on each subject's self-reported usage in the previous dispensing interval.
Bioanalytical Methodology
Urine nicotine and metabolites, total NNAL, 3-HPMA, and total 1-OHP were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods at MDS Pharma Services (Lincoln, Nebraska), and urine mutagenicity was assessed (MDS Pharma Services, Lyon, France) in a Salmonella typhimurium reverse mutation assay as reported in detail in previous publications.18,24 The 4-ABP Hb adducts in RBC were analyzed by a gas chromatography/mass spectrometry (GC/MS) method25 at Covance Laboratory (Harrogate, North Yorkshire, UK), and COHb in whole blood was measured spectrophotometrically24 at Covance Central Laboratory (Indianapolis, Indiana). Urinary 11-dehydrothromboxane B2 and 8-epi-prostaglandin F2 were determined by microplate enzyme immunoassays using commercially available kits from Cayman Chemicals (Ann Arbor, Michigan) at Covance Laboratory (Harrogate, North Yorkshire, UK).11 All assays were validated and run with appropriate calibration standards and quality control samples.26
Routine hematology and clinical chemistry, LDL and HDL cholesterol, triglycerides, bilirubin, and urinalysis were performed by the MDS Pharma Services Clinical Laboratory (Lincoln, Nebraska). Fibrinogen, hs-CRP, and von Willebrand factor antigen were analyzed at Esoterix Center for Clinical Trials (Aurora, Colorado). Clinical assay performance was monitored according to Clinical Laboratory Improvement Amendment (CLIA) guidelines.27 All clinical laboratories were CAP (College of American Pathologists) and CLIA certified.
Safety Evaluations
Physical examinations, including vital signs and electrocardiograms (ECGs), were conducted at regular intervals during the study. Adverse events and serious adverse events were documented throughout the 12-month study period.
Statistical Analysis
Descriptive statistics were provided for the biomarkers of exposure and cardiovascular risk factors. For COHb, the area under the concentration-time curve from 07:00 to 23:00 (AUC7-23 h) was calculated using numerical integration (simple trapezoidal rule). Percent change from baseline was used as outcome variable for biomarkers of exposure, and absolute change from baseline was used for cardiovascular risk factors as some baseline values were skewed to the left and were much smaller than the others. The linear mixed model for repeated-measures analysis of variance was applied for testing the difference between the 2 study groups (SAS PROC MIXED). The model included the effects of study group, study visit, and study group-by-visit interaction. It also incorporated the effect of within-subject correlation of biomarkers between study visits. The Kruskal-Wallis nonparametric test was used to test for differences among the 3 baseline measures. If no statistical difference was found among the 3 baseline measurements, the last available baseline measurement was used as the baseline value. If there was a statistical difference among the 3 baseline measurements, the average was used as the baseline value, and baseline was included as a covariate in the model. The average of all postbaseline values per group was used as postbaseline values for all group comparisons.
The statistical analysis results reported herein are based on data from all subjects with a baseline measurement and at least 1 postbaseline measurement, excluding subjects who dropped out of the study before the month 1 visit, noncompliant subjects, and subjects who had no measurable exposure data at baseline.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Of the 97 randomized subjects, 92 (95%) were evaluable (59 EHCSS, 33 CC). Five subjects in the EHCSS group were excluded from statistical analysis, 1 subject did not have any measurable exposure data at baseline, 1 subject quit smoking before the month 1 visit, and 3 subjects were not compliant and were withdrawn from the study before the month 1 visit. Ten subjects terminated the study early.
At baseline, the 2 study groups were comparable for gender, age, race, body mass index (BMI), and smoking duration (Table III).
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Cigarette Consumption
At baseline, although subjects smoked their current brand of cigarettes with 1 to 7 mg tar (FTC), there was no statistically significant difference in cigarette consumption between the study groups, with average daily consumption of 24 ± 10 (SD) cigarettes in the adult smokers randomized to the EHCSS group and 23 ± 7 in the CC group (Table IV). Over the 12 months, the mean cigarette consumption during the 24-hour clinic visits increased in both groups compared with baseline by 95% in the EHCSS group and by 27% in the CC group (P < .0001).
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Spot urine total NNAL/g creatinine excretion data and responses to queries about nonstudy cigarette use suggested that 31% of the subjects randomized to the EHCSS group had occasionally smoked conventional cigarettes in addition to the EHCSS.
Biomarkers of Exposure
Baseline data, average values over the 12-month study period, and percent change from baseline are presented in Table V. At baseline, although subjects smoked their usual brand of cigarettes with 1 to 7 mg tar delivery (FTC), mean biomarker levels were not statistically significantly different between the 2 groups, except total NNAL.
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Nicotine Equivalents and Plasma Cotinine
The 24-hour urine nicotine equivalents and plasma cotinine decreased from baseline over all 12 months by an average of 18% and 16%, respectively, in the EHCSS group, but they remained relatively stable in the CC group. The differences in mean percent change from baseline between the EHCSS and CC groups were statistically significant (P = .0014 for nicotine equivalents and P = .0018 for plasma cotinine).
Total NNAL
At baseline, the EHCSS group had a significantly lower mean urine total NNAL level (579 ng/24 h) compared with the CC group (728 ng/24 h) (P = .0077). Over all 12 months, total NNAL decreased from baseline by an average of 73% in the EHCSS group, but it remained relatively stable in the CC group (P < .0001) (Figure 1).
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Urine Mutagenicity
The mean urine mutagenicity decreased by 81% from baseline in the EHCSS group over all 12 months, compared with a 25% decrease in the CC group (P < .0001).
4-ABP Hb Adducts
4-ABP Hb adducts decreased on average by 43% in the EHCSS group and increased by 14% in the CC group (P < .0001).
Carboxyhemoglobin (COHb)
The mean COHb AUC7-23 h decreased by 80% in the EHCSS group, but it remained relatively stable in the CC group (P < .0001) (Figure 2).
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Cardiovascular Risk Factors
Hemoglobin, Hematocrit, Red Blood Cells
The mean Hb, Hct, and RBC count were not statistically significantly different between the 2 groups at baseline. Mean hemoglobin decreased from 14.5 g/dL at baseline to 14.3 g/dL postbaseline in the EHCSS group, whereas it increased from 14.7 g/dL to 14.9 g/dL in the CC group (Table VI). The difference of changes in hemoglobin from baseline between the 2 groups was statistically significant (P = .0009). Similarly, postbaseline hematocrit decreased in the EHCSS group, from 42.2% at baseline to 41.5%, and increased in the CC group from 42.2% to 43.3% (P < .0001). The RBC count in the EHCSS group remained unchanged at 4.6 x 106/µL, whereas the RBC count increased from 4.6 to 4.8 x 106/µL (P = .0172) in the CC group.
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White Blood Cells
The mean WBC count decreased from 7.5 to 6.6 x 103/µL in the EHCSS group and from 7.9 to 7.8 x 103/µL in the CC group (P = .0035) (Table VI, Figure 3). More than 75% of the subjects in the EHCSS group exhibited a decrease in white blood cell count compared with baseline. Neutrophils decreased in the EHCSS group from 4.3 to 3.4 x 103/µL and from 4.6 to 4.4 x 103/µL in the CC group (P = .0056). Lymphocytes decreased in the EHCSS group from 2.5 to 2.4 x 103/µL, whereas they remained stable in the CC group at 2.5 x 103/µL (P = .0054).
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LDL and HDL Cholesterol, Triglycerides
At baseline, no statistically significant difference between the 2 groups was found in HDL cholesterol and LDL cholesterol. Over all 12 months, mean HDL cholesterol increased by 5 mg/dL in the EHCSS group and by 1 mg/dL in the CC group (Table VII, Figure 4). The changes of HDL cholesterol from baseline in the EHCSS group were statistically significantly different compared with the changes in the CC group (P = .008). An increase in HDL cholesterol was seen in more than 75% of the subjects in the EHCSS group. LDL cholesterol decreased by 2 mg/dL in the EHCSS group, whereas it increased by 4 mg/dL in the CC group. The difference in change from baseline did not reach the level of significance but showed a trend to decrease in the EHCSS group. Triglycerides were not statistically significantly different at baseline but showed a clinically meaningful difference (Table VII). There was a slight increase in triglycerides in the EHCSS group and a slight decrease in the CC group postbaseline.
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Fibrinogen, hs-CRP
Over the 12-month study period, mean fibrinogen decreased by 13 mg/dL, and mean hs-CRP decreased by 0.3 mg/dL in the EHCSS group, whereas these biomarkers stayed rather stable in the CC group (Table VII). The changes in fibrinogen and hs-CRP in the EHCSS group were not statistically significantly different compared with the changes in the CC group (fibrinogen P = .22; hs-CRP P = .17).
11-Dehydrothromboxane B2, 8-epi-Prostaglandin F2
In the EHCSS group, urine 11-dehydrothromboxane B2 decreased from 1826 ng/24 h at baseline to 1450 ng/24 h, but it remained relatively stable in the CC group (Table VII, Figure 5). The difference in the changes between the 2 groups was statistically significant (P = .0031). Eighty percent of the subjects in the EHCSS group had a decrease in 11-dehydrothromboxane B2 excretion. Mean 8-epi-prostaglandin F2 excretion increased in both groups over the 12-month study period but to a larger extent in the CC group (P = .33).
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Safety Results
Sixty-five of the 97 subjects (67%) reported at least 1 adverse event (AE) over the 12-month study period, with headache being the most commonly experienced AE. No product-related trends were noted in the adverse events, physical examinations (including vital signs and larynx examination), clinical chemistry, urinalysis, or ECG findings.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The randomized, controlled study design with forced switching to a PREP has limitations because smokers in the control group could continue their usual smoking behavior with a similar conventional cigarette, whereas smokers in the EHCSS group had to switch to a very different product with a cigarette smoked in a heater the size of a cigarette pack with different taste, were limited to 8 puffs per cigarette, and had to adjust their smoking ritual. Because of this and the length of the study, we expected more subjects to drop out of the EHCSS group, so we oversampled the EHCSS group in a 2:1 ratio and allowed all participants to try the EHCSS in the screening period before randomization. In total, 50/64 (78%) of adult smokers randomized to the EHCSS group and 32/33 (97%) randomized to the CC group completed all study visits. Most of the evaluations were conducted under confined, controlled clinical conditions to ensure complete 24-hour urine collections and repeated blood sampling over the day for COHb. To assess compliance with exclusive use of the EHCSS, we checked urine total NNAL excretion at biweekly intervals throughout the 12-month study period. NNAL, a tobacco-specific biomarker of exposure with a relatively long elimination half-life,18 has been shown to be substantially reduced while smoking the EHCSS.18,24 Values of total NNAL >400 ng/g creatinine suggested use of conventional cigarettes in the previous 2 weeks based on data from a previous short-term exposure study.18
Despite a substantially different smoking experience with EHCSS compared with CC, 41/59 (69%) of the evaluable EHCSS smokers appeared to have used the EHCSS exclusively during the entire study. The fact that not all smokers in the EHCSS smoked the EHCSS exclusively should be considered when interpreting the study results.
Biomarkers of Exposure
Near-maximal reductions in all biomarkers of exposure were observed at the first assessment time point at 2 weeks after switching to the EHCSS and were sustained over the 12-month study period. These reductions occurred despite a 95% increase in cigarette consumption, on average, over the 12 months in real-life smoking conditions. A limitation to the cigarette consumption data in the current study is that it was self-documented only during the investigational visits in a clinical setting and may not accurately reflect consumption during routine daily activities. By comparison, the magnitude of reductions in most biomarkers of exposure over the 12 months was somewhat less than that seen in a previously reported 8-day exposure study using this second-generation EHCSS.18 This may be due to different cigarettes the adult smokers smoked before switching to the EHCSS. In the 8-day exposure study, smokers had smoked 11-mg tar (FTC) cigarettes, whereas in this study, they had smoked 1-to 7-mg tar (FTC) cigarettes. In addition, the subjects were confined in the 8-day exposure study, and cigarette consumption was limited to the EHCSS only.
Of note, urine mutagenicity, which is also affected by diet, decreased significantly in the EHCSS group compared with the CC group despite unrestricted diet conditions. Urine mutagenicity may thus be a useful biomarker to differentiate tobacco products even in subjects' normal life settings.
Cardiovascular Risk Factors
Several cardiovascular risk factors, including WBC counts and its subpopulations and 24-hour urine 11-dehydrothromboxane B2, decreased significantly in subjects who switched to EHCSS compared with the CC group. Fibrinogen, hs-CRP, and LDL cholesterol decreased, too, but these changes did not reach the level of statistical significance. This may be due to the small size of the study groups. HDL cholesterol increased significantly in the EHCSS group compared with the CC group. These changes in cardiovascular risk factors were found to occur within 2 weeks following switching, were maximal at month 3, and were sustained through the entire study period.
Increased levels of hemoglobin and hematocrit have been found to be associated with cigarette smoking,28,29 perhaps to compensate for higher COHb concentrations. It was reported in a smoking reduction study that both hemoglobin and hematocrit improved (decreased significantly) at week 6 while subjects reduced their daily cigarette consumption by 40%.29 In the present study, both hemoglobin and hematocrit levels were significantly decreased after switching to the EHCSS compared with the CC group. This is likely the result of a significant reduction in exposure to CO as demonstrated by the substantial decrease in COHb.
Low-grade systemic inflammation, as characterized by elevated WBC counts, C-reactive protein, and fibrinogen, has been reported to be associated with cigarette smoking and coronary heart disease.30 In the current study, we found a significant reduction of WBC and its subpopulations in smokers switched to the EHCSS, as well as a trend for reduction of fibrinogen and hs-CRP. These results are similar to those observed in studies targeting the association between the degree of exposure to cigarette smoke and WBC counts. In a study of 58 adult smokers who participated in a 16-week smoking reduction/cessation study, 50% reduction in daily cigarette consumption resulted in a significant decrease of WBC counts alongside a reduction of fibrinogen.12 Abstinence from smoking further decreased WBC counts. The odds ratio for the highest WBC count quartile increases with the amount of daily cigarettes smoked in current smokers.31
Platelet activation plays an important role in the initiation of thrombosis. Previous studies have shown that platelets are activated during chronic cigarette smoking. The excretion of thromboxane B2, a major urinary thromboxane metabolite, is elevated in smokers compared with nonsmokers.32 In the present study, urine 11-dehydrothromboxane B2 decreased significantly in smokers who switched to EHCSS, indicating a reduction in platelet activation.
HDL cholesterol is a well-established major protective factor against coronary heart disease.33 HDL cholesterol levels are lower in smokers.7 A meta-analysis of 54 published studies revealed a dose-dependent relationship between HDL cholesterol and the amount of cigarettes smoked. HDL cholesterol concentrations were -4.6%, -6.3%, and -8.9% lower in light, moderate, and heavy smokers, respectively, compared with nonsmokers.7 In a large cross-sectional study, a stepwise decrease of serum HDL cholesterol levels was found as the number of cigarettes smoked per day increased, but no difference was found for LDL cholesterol.4 In another study, it was found that HDL cholesterol increased 4.5% from baseline and LDL cholesterol decreased 3.6% following 1 week of smoking cessation.34,35 In the present study, we found that the HDL cholesterol level increased by 13.5% from baseline in subjects who switched to the EHCSS.
In a previous study,11 we evaluated biomarkers of exposure and cardiovascular risk factors in nonsmokers and in adult smokers of cigarettes comparable to those smoked in the current study at baseline and in the CC control group. The results found in the present study for the CC control group are in line with those in smokers of that study. The absolute changes in cardiovascular risk factors seen after switching to the EHCSS indicate a 40% to 90% shift from the values in smokers toward those observed in nonsmokers in that study.11
Conclusions
We found substantial reductions in exposure to smoke constituents associated with significant changes in cardiovascular risk factors when adult smokers switched to the EHCSS for 12 months. The changes indicate improvement in hemorrheology (RBC, Hct, Hb) and lipid metabolism (HDL cholesterol), as well as reduction in inflammation (WBC, fibrinogen, hs-CRP), platelet activation (11-dehydrothromboxane B2), and lipid peroxidation (8-epi-prostaglandin F2).
This study is the first to prove the feasibility of changing cigarettes to reduce exposure to cigarette smoke constituents and to show that the use of such a reduced-exposure product is associated with significant, clinically meaningful, measurable reduced risk for cardiovascular disease compared with the continued smoking of conventional cigarettes. Larger studies of longer duration are needed to confirm these results for the EHCSS and to investigate the effects on other smoking-related diseases, particularly chronic obstructive pulmonary disease and lung cancer.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: Financial support provided by Philip Morris USA.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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