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PHARMACOKINETICS |
From the Departments of Clinical Pharmacokinetics and Pharmacodynamics (Dr Faessel, Dr Gibbs, Mr Rohrbacher), Medical and Developmental Sciences (Dr Faessel, Dr Gibbs, Dr Clark, Mr Rohrbacher, Dr Burstein), and Statistics (Dr Stolar), Pfizer Global Research and Development, Groton, Connecticut.
Address for reprints: Hélène M. Faessel, PharmD, PhD, Pfizer Global Research and Development, Eastern Point Road/MS 8260-2309, Groton, CT 06340; e-mail: Helene.M.Faessel{at}pfizer.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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4ß2 nicotinic acetylcholine receptor partial agonist developed for smoking cessation. The primary objectives of this double-blind, placebo-controlled, dose-escalation study were to determine the pharmacokinetics, safety, and tolerability of multiple oral doses of varenicline given as tablets once (1 mg, 2 mg, and 3 mg) or twice (1 mg) daily to healthy adult smokers. Within each dose level, 8 subjects were randomized to varenicline and 4 subjects to placebo. Varenicline was well tolerated at doses up to and including 2 mg daily. Dose-proportional increases in maximum observed plasma concentrations and area under the plasma concentration-time curve from time zero to the end of the dosing interval values were observed between the 1-mg and 2-mg daily doses of varenicline. Once- and twice-daily dosing resulted, on average, in an approximate 2- and 3-fold increase in varenicline systemic exposure, respectively, compared with single dose. There was no evidence of concentration- or time-dependent changes in the pharmacokinetics of varenicline upon repeat dosing.
Key Words: Varenicline • multiple dosing • pharmacokinetics
Varenicline is a potent and selective 4ß2 nicotinic acetylcholine receptor partial agonist (nAChR) developed as an aid to smoking cessation (Figure 1).6 Because of its mixed agonist-antagonist effects, varenicline is expected to reduce the psychogenic reward associated with smoking while also relieving nicotine craving and withdrawal symptoms during abstinence.
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After administration to healthy volunteers, varenicline was well tolerated up to single doses of 3 mg in smokers and 1 mg in nonsmokers.11 Varenicline single-dose pharmacokinetics were similar in both populations, whereas food did not affect varenicline pharmacokinetics.11
The objective of this study was to determine the clinical pharmacology of multiple oral doses of varenicline given once or twice daily to healthy smokers. In addition, the effect of varenicline on pharmacodynamic measures of smoking status (number of cigarettes smoked, nicotine and cotinine concentrations) was examined.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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10 cigarettes smoked per day, confirmed by urine cotinine levels >500 ng/mL) were enrolled in the study. Females must have been of nonchildbearing potential, that is, surgically sterilized or at least 2 years postmenopausal, and not breastfeeding. Subjects ranged in age from 18 to 45 years, in height from 162.2 to 188.0 cm, and in body weight from 53.7 to 91.5 kg. All participants had a normal renal function for their age, that is, creatinine clearance of at least 80 mL/min, as estimated by the method of Cockroft and Gault.12 Smokers must have had a Fagerström Nicotine Dependence Rating of 6 or higher. There was no restriction on smoking. The study was conducted at one clinical site, and approved by PPD Development Clinic Independent Ethics Committee, 72 Hospital Close, Evington, Leicester, LE5 4WW, United Kingdom. All subjects gave written informed consent to participate prior to undergoing any study procedures. Alcohol, caffeine, and grapefruit juice were not permitted, beginning 48 hours prior to the start of the study through the completion of the study.
Study Design
This was a double-blind, placebo-controlled, multiple-dose, dose-escalation study, with doses administered once or twice a day. The initial plan involved dosing a cohort of subjects with 1 mg varenicline once daily. The next group of subjects received 3 mg once daily. Because of tolerability issues, 2-mg once-daily and 1-mg twice-daily groups were subsequently investigated. Overall, 4 dose levels were studied (1 mg, 2 mg, and 3 mg once daily and 1 mg twice daily). Within each dose level, 8 subjects were randomized to varenicline and 4 subjects to placebo. For the once-daily dose regimen, drug administration occurred in the morning. Placebo was administered on day 0, followed by the administration of varenicline or placebo on day 1. On days 2 and 3, placebo was administered. Starting on day 4, varenicline or placebo was administered once daily for a total of 14 days. Placebo dosing was continued up to the morning administration on day 22 in all subjects. For the twice-daily dose regimen, drug administration occurred in the morning and evening (every 12 hours). Placebo was administered on day 0, followed by the administration of varenicline or placebo twice daily for 14 days. Placebo was then continued up to the morning administration on day 19 in all subjects.
Test Drugs and Administration
Dosage and administration. Study drug (varenicline succinate or placebo) was supplied as immediaterelease tablets. A total volume of 180 mL water was consumed with the tablets. The sponsor provided specific dosing instructions to the site. All blinded doses were prepared by an unblinded member of the Clinical Research Unit (CRU) staff with appropriate training and experience and who was not responsible for other aspects of the study.
Once-daily dosing. For the 1- and 3-mg once-daily groups, subjects were dosed in the morning at approximately 8:00 AM following an overnight fast of at least 8 hours. For the 2-mg once-daily group, subjects fasted for at least 8 hours prior to consuming a standard (not high-fat) breakfast. The breakfasts on days 1 and 17 were identical and completely ingested within a 20-minute period. Subjects were dosed immediately after the meal at approximately 8:00 AM. On other days, a regular breakfast was consumed just before dosing. The daily nutritional composition was 
50% carbohydrates, 35% fat, and 15% protein. To standardize experimental conditions, all subjects were required to refrain from lying down (except for vital sign and electrocardiographic [ECG] measurements), eating, and drinking beverages other than water during the first 4 hours after drug administration on days 1 and 17 (or day 11 for the 3-mg once-daily group).
Twice-daily dosing. For the 1-mg twice-daily group, subjects fasted for at least 8 hours prior to consuming a standard (not high-fat) breakfast. The breakfasts on days 1 and 14 were identical and completely ingested within a 20-minute period. Subjects were dosed at approximately 8:00 AM immediately following the meal. In the evening, subjects fasted for at least 2 hours prior to consuming a standard (non high-fat) dinner. The dinners on days 1 and 14 were identical and completely ingested over a 30-minute period. Subjects were dosed at approximately 8:00 PM immediately following the meal. The daily nutritional composition was 50% carbohydrates, 35% fat, and 15% protein. On other days, standard breakfast and dinner were consumed just before dosing. To standardize experimental conditions, all subjects were required to refrain from lying down (except for vital sign and ECG measurements; morning dosing only), eating, and drinking beverages other than water during the first 4 hours after drug administration on days 1 and 14.
Analytical Methods
Plasma collection. For the once-daily dosing groups, blood samples sufficient to provide a minimum of 3 mL plasma for pharmacokinetic analysis of varenicline (day 1) were collected predose and nominally at 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and 72 hours into appropriately labeled green-top tubes containing sodium heparin following single oral administration of varenicline. For the multiple-dose phase, blood samples were collected for pharmacokinetic analysis of varenicline predose and nominally at 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, and 144 hours following the last dose of varenicline on day 17. For the 3-mg once-daily group, the last day of the multiple-dose phase was day 11, and no samples were drawn at 0.5 and 1 hour postdose. In addition, a single predose sample was obtained immediately prior to dosing on days 6, 7, 8, 11, and 14 for the 1- and 2-mg once-daily groups, and on days 6, 7, 8, and 11 for the 30-mg once-daily group.
For the twice-daily dosing group, blood samples sufficient to provide a minimum of 3 mL plasma for pharmacokinetic analysis of varenicline (day 1) were collected predose and nominally at 0.5, 1, 2, 4, 8, 12 (just before the evening dose), 12.5, 13, 14, 16, and 20 hours into appropriately labeled green-top tubes containing sodium heparin following the morning drug administration of varenicline. For the multiple-dose phase, blood samples were collected for pharmacokinetic analysis predose and nominally at 0.5, 1, 2, 4, 8, 12 (just before the evening dose), 12.5, 13, 14, 16, 20, 24, 36, 48, 72, 96, and 144 hours following the last dose of varenicline on day 14. Additional blood samples were drawn predose (immediately prior to morning dosing) on days 2, 3, 4, 5, 8, and 11 and at 12 hours (just before the evening dosing) on days 2, 5, 8, and 11.
Blood samples were centrifuged (at 1700g) for 10 minutes at approximately +4°C. The resultant plasma was stored in appropriately labeled screw-capped polypropylene tubes at -20°C or lower within 1 hour of collection.
Urine collection. For all 4 dosing groups, urine was collected over the 2 periods of 0 to 24 hours and 24 to 48 hours after single and repeat oral administration of varenicline. However, for the first 24-hour period (0-24 hours), urine was collected over 3 intervals (0-6 hours, 6-12 hours, and 12-24 hours). At the end of each urine collection period, the total volume was measured and recorded. The urine was then mixed thoroughly and a 5-mL aliquot from each collection period was retained, labeled, and frozen at -20°C until analysis. Aliquots necessary for urine electrolytes were also withdrawn from the same samples.
Assay method. Plasma and urine samples were analyzed for varenicline concentrations using a fully validated high-performance liquid chromatography-atmospheric pressure ionization/tandem mass spectrometry assay (LC-API/MS/MS) following liquid-liquid extraction, as described previously,11 with the following modification: the high-performance liquid chromatography system consisted of a Hypersil BDS-CPS Column, 100 mm x 2.1 mm, 5-µm particle size. The PE SCIEX API 3000 triple quadrupole mass spectrometer (Applied Biosystems, Foster City, Calif) was operated in the positive ion mode and adjusted to monitor parent to product ion transitions of mass-to-charge ratio (m/z) 212.1 to 168.0 for drug (varenicline) and m/z 240.1 to 198.0 for the internal standard (CP-533,633). The dynamic range of the plasma assay was from 0.100 to 50.0 ng/mL. Plasma varenicline concentrations below the lower limit of quantification (LLOQ) were reported as <0.100 ng/mL and assigned a value of 0.0 ng/mL for calculation of summary statistics. The interassay accuracy and precision were determined by analyzing 3 different quality control samples in replicates of 5 on 3 days. The interassay mean accuracies (and precision) were 91% (5.1%), 97% (6.2%), and 100% (6.2%) at the 3 quality control plasma concentrations. For urine, the assay had a dynamic range of 1.00 to 500 ng/mL and an LLOQ of 1.00 ng/mL using a 1-mL sample volume. The interassay mean accuracies (and precision) were 95% (9.0%), 99% (7.2%), and 103% (5.8%) at the 3 quality control urine concentrations.
Pharmacokinetic Evaluation
Individual plasma concentration-time data for varenicline obtained on day 1 after single-dose administration and day 17 (or day 11 for the 3-mg dose group) after once-daily dosing and day 14 after twice-daily dosing were analyzed by standard noncompartmental methods using the custom software PK_PARAM2 (internally developed by Pfizer Inc, Groton, Conn). Maximum observed plasma concentrations (Cmax), trough plasma concentration (Cmin), and the time to reach Cmax (tmax) were obtained directly from the experimental data. The partial area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUC0-
), where was the dosing interval time equal to 12 hours (twice-daily regimen) or equal to 24 hours (once-daily regimen) was estimated using the linear trapezoidal approximation. The apparent elimination rate constant (Kel) was estimated using linear least squares regression analysis of the plasma concentration-time data obtained during the terminal log-linear phase. The apparent terminal phase half-life (t
) was calculated as ln(2)/Kel. Renal clearance (CLr) was calculated using urinary excretion data obtained after single and repeat dosing, as the total amount of unchanged drug eliminated in urine (Ae) in t = 12 or 24 hours divided by plasma AUC0-t, where t was equal to 12 or 24 hours, respectively. In addition, the observed accumulation ratio (Ro) was determined, as the ratio of AUC0- on the last day of administration to AUC0- on day 1, to assess changes in systemic exposure following repeat administration relative to single dosing.
The attainment of steady-state conditions was visually assessed from the graphical representations of plasma predose concentrations of varenicline measured immediately prior to dosing on days 6, 7, 8, 11, 14, and 24 hours after dosing on day 17 (1 and 2 mg once daily), on days 6, 7, 8, 11, and 24 hours after dosing on day 11 (3 mg once daily), and on days 2, 3, 4, 5, 8, 11, and 12 and 24 hours after dosing on day 14 (1 mg twice daily).
Mean plasma concentrations were determined at each nominal sampling time point only when individual values were above the LLOQ (0.100 ng/mL) in more than 50% of the subjects receiving a given dose. All pharmacokinetic parameters are reported as arithmetic mean ± standard deviation, except tmax is given as median (range).
Safety
The safety and tolerability of varenicline were assessed in all the volunteers by clinical observation and spontaneous reporting of adverse events by subjects. Vital signs, physical examinations, ECG recordings, and clinical laboratory measurements were monitored throughout the study. For subjects receiving study medication once daily, vital signs were measured once at screening (day -1), on day 0 and day 1 at 0 (just prior to the initial placebo dose) and 2 hours postdose, and then on days 6, 11, 17 (2 hours postdose), and day 22 (24 hours after dosing). For subjects receiving study medication twice daily, vitals signs were measured once at screening (day -1), on day 0, and day 1 at 0 (just prior to morning dosing), 3 and 15 hours after morning dosing, then on days 4, 7, and 14, at 3 and 15 hours after morning dosing, and on day 19 (24 hours after dosing). A 12-lead ECG was obtained in subjects receiving study medication once daily at screening (day -1), on day 0 at 0 hour (just prior to the initial placebo dose), then on days 1, 6, 11, 17 (2 hours postdose), and day 22 (24 hours after dosing). For subjects receiving study medication twice daily, a 12-lead ECG was obtained at screening, on day 0 at 0 hour (just prior to morning dosing) and 15 hours after morning dosing and then on days 1, 4, 7, and 14, at 3 and 15 hours after morning dosing, and on day 19 (24 hours after dosing). Laboratory tests were performed at screening, on days 1, 4, 6, 8, 11, 14, 17, 18, day 20 at 0 hour (just prior to dosing), and day 22 (24 hours after dosing) for subjects dosed once daily; and at screening and days 1, 3, 5, 7, 11, 14, 15, 17, and 20 at 0 hour (just prior to dosing) for subjects dosed twice daily.
Pharmacodynamic Evaluation
Plasma nicotine/cotinine level. Blood sufficient to provide a minimum of 3 mL plasma for nicotine and cotinine measurements was collected at screening, approximately 4:00 PM on day -1 (16 hours prior to the initial placebo dose). Additional samples were collected at approximately 4:00 PM (8 hours after dosing with study medication) on days 0 through 6, 8, 11, 14, and 17 through 22 following once-daily dosing, and on days 0 through 3, 5, 8, 11, and 14 through 19 following twice-daily dosing.
Smoking record. The number of cigarettes smoked during the study was recorded daily. Subjects smoked their usual brand of cigarette, and the brand of the cigarette and its nicotine content were also recorded; subjects were not asked to change their smoking habits.
Statistics
No specific statistical hypothesis tests were planned in the protocol. For the purpose of this article, however, a post hoc analysis of dose proportionality was performed. The power model method described in Gough et al,13 in which the logarithm of the pharmacokinetic parameter (Cmax, AUC) is linearly related to the logarithm of dose, was used to estimate the ratio of geometric means between doses and the corresponding confidence interval.
Pharmacokinetic, pharmacodynamic, and safety data were summarized through appropriate data tabulations, descriptive statistics, and graphical presentations.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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During the multiple-dose phase, there were no deaths; 1 subject in the placebo twice-daily group had a serious adverse event, and 5 subjects taking once-daily doses were discontinued because of adverse events. One subject (2 mg varenicline once daily) and 4 subjects (3 mg varenicline once daily) were withdrawn because of mild to moderate vomiting, which resolved shortly after the last dose of study medication. Greater than 1 adverse event was experienced by 93% of subjects receiving varenicline and 86% of subjects receiving placebo. Because of a high incidence of early onset of nausea and vomiting observed at the 3-mg once-daily/placebo-dose level (unblinding of the data reveals this occurred in all subjects receiving 3-mg once-daily varenicline), the dosing was halted on day 11 after 8 days of continuous dosing. Thus, the daily dose to be investigated in the subsequent dose group was reduced to 2 mg varenicline administered orally once or twice daily following a standard (not high-fat) meal. The incidence of nausea and vomiting in the 2-mg once-daily fed group was less than that in the 3-mg once-daily group dosed under fasted conditions. When the 2-mg daily dose was administered as a divided dose (1 mg twice daily) with food, nausea was reported in only 1 subject and vomiting was not seen. Overall, there was no apparent effect of varenicline on clinical laboratory assessments, vital signs (blood pressure and heart rate), QTc, or ECG morphology.
Multiple-Dose Pharmacokinetics in Smokers
As shown in Figure 2 (A and B), mean plasma varenicline concentrations were higher after repeat dosing compared to single-dose administration for all dose groups, indicating drug accumulation following once- or twice-daily oral administration of varenicline. Relevant pharmacokinetic parameters for varenicline and associated summary statistics are presented for each dose regimen in Table I. Maximum plasma varenicline concentration was achieved within 2 to 4 hours postdose for each regimen following both single and multiple doses of varenicline. After attaining Cmax, concentrations of varenicline were generally detectable in plasma between 96 and 144 hours after 1-mg and 2-mg once-daily dosing and up to 144 hours following 3-mg once-daily and 1-mg twice-daily dosing. Although not a primary objective in this study, dose proportionality was investigated using the power model method based on dose-normalized Cmax and AUC geometric means. Dose-proportional increases in mean Cmax and AUC0- values were observed between the 1- and 2-mg dose levels after single- and once-daily dosing (Table II). Because varenicline was not tolerated in all the subjects receiving 3 mg once daily, individual systemic exposures could not be accurately determined in this group. In fact, the slightly lower than expected increase in mean systemic exposure to varenicline is consistent with the expectation that vomiting would reduce the drug systemic availability (Table I). The elimination phase was adequately characterized in most subjects and individual t values ranged between 16 and 27 hours following single dosing and between 18 and 43 hours after repeat dosing (Table I). In subjects in which AUC0- could be determined, the parameter was well described as the percentage of extrapolated area that was 16% or less. Mean estimates of CLr for varenicline were comparable across all dosing regimens, on both study days, ranging between 88 to 155 mL/min after single administration and between 92 and 143 mL/min after repeated administration (Table I).
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The mean (±SD) plasma trough concentration-time profiles for varenicline for each dose group from day 2 to day 14 of the multiple-dose phase are shown in Figure 3. Visual inspection of the mean and individual plasma trough concentration-time profiles at each dose level showed that steady-state conditions appeared to have been reached by day 4, as evidenced by the plateau in the varenicline plasma trough concentrations measured from day 4 onward. Observed systemic accumulation of varenicline appeared to be independent of dose (Table I). The overall mean accumulation factor following 1-, 2-, and 3-mg once-daily dosing was 1.94 ± 0.31. After 14 days of twice-daily dosing, the observed drug accumulation was, on average, 2.85 ± 0.73. When calculating steady-state accumulation as AUC0- at steady state divided by AUC0- on day 1, the ratio was found to be nearly 1 for all 3 once-daily dose regimens. Thus, the pharmacokinetics of varenicline does not exhibit time and concentration-dependent phenomena upon repeat dosing. Furthermore, diurnal variation was examined in the 1-g twice-daily group by comparing pharmacokinetic parameters during the second dosing interval to the first dosing interval at steady state. Mean ratios for AUC0- and Cmax were 1.1 and 1.0, respectively. Median tmax was 2 hours after the morning dose and 3 hours after the second dose in the evening.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Maximum plasma varenicline concentration was achieved typically within 4 hours postdose for each regimen on both study days. Dose-proportional increases were observed in systemic exposure, based on Cmax and AUC0- values, after single and repeat dosing between the 1-mg and 2-mg doses of varenicline.
Mean elimination half-life of varenicline appears to be similar following single (t = 21.4 ± 3.3 hours) and repeat (t = 26.1 ± 5.5 hours) dose administration of varenicline. Individual t estimates were generally comparable to the values reported at the 3- and 10-mg doses in the single-dose study, where the terminal phase could be adequately characterized.11 Consistent with this t of approximately 24 hours, steady-state conditions were reached within 4 days of repeated administration of varenicline. Once-daily dosing resulted in an approximate 2-fold increase on average in systemic exposure to varenicline with the observed accumulation ratio being consistent across all 3 doses. When varenicline was administered twice daily, systemic exposure was increased, on average, about 3-fold over the 12-hour dosing interval. The extent to which varenicline systemic exposure increased at steady-state could be well predicted from the single-dose pharmacokinetic data. There was no evidence of concentration- or time-dependent changes in the pharmacokinetics of varenicline upon repeat dosing.
In rat, monkey, and mouse, more than 88% of [14C]-varenicline was recovered in the urine.14 Consistent with excretion data obtained in preclinical species, high amounts of varenicline were recovered in urine in this study. Estimates of renal clearance were similar across treatments and study days, indicating that the elimination process of varenicline was not altered upon repeat dosing. Also in this study, renal function was estimated to be on average between 106 and 112 mL/min (individual creatinine clearance range, 78.5-140) across the dose groups. Varenicline is a low (
20%) protein bound compound in plasma. Thus, with unbound renal clearance estimates (110-193 mL/min) that slightly exceed the subject's glomerular filtration rate, it can be suggested that active secretion of varenicline may be operative in some subjects.15 Based on the present results, as well as information from the human radiolabeled absorption, distribution, metabolism, and excretion (ADME) study, it appears as though varenicline, a small organic compound, is almost exclusively renally cleared in humans.14 Indeed, the presence of almost all radioactivity in urine as unchanged drug (>90%), with the remaining material eliminated in the urine as metabolites, indicates that varenicline does not undergo significant hepatic metabolism in humans and is virtually completely absorbed with high systemic availability after oral administration.
The pharmacodynamic assessments obtained in this multiple-dose study provide initial indications of the pharmacologic activity of varenicline at the 4ß2 nicotinic acetylcholine receptor. The number of cigarettes smoked decreased noticeably at daily doses of 2 and 3 mg varenicline. This decrease was seen after 2 to 4 days of dosing. Concomitant decreases in plasma cotinine and nicotine levels were also observed. Consistent with previous reports,7,8 cotinine, the primary metabolite of nicotine, was present in much higher concentrations (on average, 250-350 ng/mL) in plasma than those of nicotine. Cotinine is widely used as a biomarker of daily nicotine intake, because cotinine concentrations in the plasma and urine of cigarette smokers are more stable, as a result of its longer half-life, than nicotine levels are throughout the day. In addition, cotinine is metabolized to 3'-hydroxycotinine (3-HC) by the same enzyme responsible for the metabolism of nicotine.10 Findings by Benowitz et al9,10 demonstrated that the rate of nicotine metabolism determines the level of cigarette consumption. That is, the higher the ratio of 3-HC:cotinine, the faster the clearance of nicotine and the greater the need to smoke more to maintain adequate levels of nicotine in the body. In this study, a spontaneous reduction in smoking as evidenced by concomitant decreases in nicotine and cotinine levels and cigarette consumption was shown at doses of varenicline of 2 mg/d or greater. This pharmacodynamic effect was observed in a healthy volunteer population, not intending on smoking cessation. Based on these promising pharmacokinetic and pharmacodynamic results, varenicline was progressed further into clinical development to evaluate its efficacy and safety for smoking cessation.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was funded by Pfizer Inc. Hélène M. Faessel, Megan A. Gibbs, David J. Clark, Kevin Rohrbacher, Marilyn Stolar, and Aaron H. Burstein are employees of Pfizer Inc.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Ezzati M, Lopez AD. Estimates of global mortality attributable to smoking in 2000. Lancet. 2003;362: 847-852.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years' observations on male British doctors. Br Med J. 2004;328: 1519.
3. World Health Organization. Quantifying Selected Major Risks to Health. World Health Report 2002. Geneva, Switzerland: World Health Organization; 2002. Available at: http://www.who.int/whr/2002/en/whr02_ch4.pdf.
4. Benowitz NL. Pharmacology of nicotine addiction: addiction and therapeutics. Annu Rev Pharmacol Toxicol. 1996;36: 597-613.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Benowitz NL. Nicotine addiction. Prim Care. 1999;26: 611-631.[Web of Science][Medline] [Order article via Infotrieve]
6. Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an 4ß2 nicotinic receptor partial agonist for smoking cessation. J Med Chem. 2005;48: 3474-3477.[CrossRef][Web of Science][Medline]
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7. Hukkanen J, Jacob P III, Benowitz NL. Metabolism and disposition kinetics of Nicotine. Pharmacol Rev. 2005;57: 79-115.
8. Benowitz NL, Jacob P III. Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther. 1994;56: 483-493.[Web of Science][Medline] [Order article via Infotrieve]
9. Benowitz NL, Pomerleau OF, Pomerleau CS, Jacob P III. Nicotine metabolite ratio as a predictor of cigarette consumption. Nicotine Tob Res. 2003;5: 621-624.
10. Benowitz NL, Jacob P III. Disposition kinetics, effects and plasma levels during cigarette smoking. Br J Clin Pharmacol. 2001;51: 53-59.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Faessel HM, Obach RS, Gibbs MA, Smith B, Clark DJ, Burstein AH. Single-dose pharmacokinetics of varenicline, a nicotinic receptor partial agonist, in healthy smokers and nonsmokers. J Clin Pharmacol. In press.
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13. Gough K, Hutchison M, Keene O, Byrom B, Ellis S, Lacey L, McKellar J. Assessment of dose proportionality: report from the statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Working Party. Drug Inf J. 1995;29: 1039-1048.
14. Obach RS, Reed-Hagen AE, Krueger SS, et al. Metabolism and disposition of varenicline, a selective 4ß2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug Metab Dispos. 2006;34: 121-130.
15. Rowland M, Tozer TN. Clinical Pharmacokinetics. Philadelphia, Pa: Lea & Febiger; 1989.
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