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Pharmacokinetics, Safety, and Tolerability After Single and Multiple Oral Doses of Varenicline in Elderly Smokers

From the Departments of Medical and Developmental Sciences (Dr Burstein, Dr Fullerton, Dr Clark, Dr Faessel), and Clinical Pharmacokinetics and Pharmacodynamics (Dr Faessel), Pfizer Global Research and Development, Groton, Connecticut. This study was funded by Pfizer Inc. Aaron H. Burstein, Terence Fullerton, David J. Clark, and Hélène M. Faessel are employees of Pfizer Global Research and Development.

Address for reprints: Aaron H. Burstein, PharmD, Pfizer Global R&D, Groton/New London Labs, Eastern Point Road, MS8260-2505, Groton, CT 06340.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Varenicline is a novel selective 4ß2 nicotinic acetylcholine partial agonist developed for smoking cessation. This study investigated the single- and multiple-dose pharmacokinetics, safety, and tolerability of varenicline in elderly ( 65 years) smokers. Twenty-four elderly smokers with normal renal function for their age (estimated creatinine clearance 70 mL/min) received varenicline 1 mg once daily (n = 8) or placebo (n = 4) for 7 days, or 1 mg twice daily (n = 8) or placebo (n = 4) for 6 days with a single dose on day 7 in a double-blind, parallel group and placebo-controlled design. There was no evidence of concentration- or time-dependent changes in varenicline pharmacokinetics upon repeat dosing. Once- and twice-daily dosing was associated with an approximate 2-fold and 3-fold increase, respectively, in systemic exposure to varenicline. Varenicline was well tolerated; all adverse events reported were mild to moderate in intensity. Thus, no dose adjustment is necessary based on age alone.

Key Words: Varenicline • elderly • single- and multiple-dose pharmacokinetics

Nicotine modifies behavior and mediates dependence by stimulating the predominant 4ß2 nicotinic acetylcholine receptor (nAChR) in the mesolimbic system of the brain.^6-8 More recent findings from Maskos et al⁹ provide decisive evidence that the ß2-subunit containing nAChR located in the ventral tegmental area of the midbrain plays a crucial role in the dependence productive effects of nicotine. Activation of the mesolimbic neurons, which project into the nucleus accumbens, results in an increase in dopamine release, which triggers the rewarding and reinforcing effects associated with smoking. Abstinence from smoking often results in craving and withdrawal symptoms, leading to high relapse rates in those attempting to quit.

Varenicline is a novel selective nAChR partial agonist that binds specifically to the 4ß2 nAChR. As a partial agonist, varenicline partially activates this receptor with sufficient pharmacologic efficacy so as to minimize craving and withdrawal symptoms in abstinent subjects. By also inhibiting nicotine binding at the receptor, varenicline should mitigate the reinforcing and rewarding effects of smoking in those persons who continue to smoke. The efficacy and safety of varenicline as a smoking cessation therapy have been clinically established in adult smokers.

Phase 1 studies in smoking and nonsmoking adults aged between 18 and 45 years old have already described the pharmacokinetic profile of varenicline.^10,11 With single-dose oral administration of varenicline, smokers and nonsmokers tolerated up to 3 and 1 mg, respectively; nausea and vomiting were the dose-limiting effects. With multiple-dose oral administration, 2 mg/d was the maximum tolerated dose in smokers. Varenicline exhibits linear kinetics when given as single or repeated doses up to 3 mg/d in smokers.^10,11 Maximum plasma concentration of varenicline typically occurred within 3 to 4 hours after oral administration. Based on absorption, distribution, metabolism, and excretion (ADME) information, varenicline is almost exclusively excreted via the kidney. Varenicline is virtually completely absorbed after oral administration, with high (>90%) systemic availability based on recovery of unchanged drug in urine.¹² Consistent with a terminal elimination half-life (t) of approximately 24 hours, steady-state conditions of varenicline are reached within 4 days, and accumulation upon multiple dosing is predictive from single dosing. Oral bioavailability is unaffected by food or time-of-day dosing.¹⁰ In phase 2 studies, varenicline has been shown to be effective and well tolerated in smokers aged up to 65 years.¹³

It can be anticipated that a considerable number of elderly smokers will use pharmacologic aids such as varenicline in an attempt to stop smoking. Hence, the present study was performed to investigate the single- and multiple-dose pharmacokinetics of varenicline in male and female elderly smokers; a second objective was to evaluate the safety and tolerability of varenicline in this population.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The study was conducted in accordance with the Declaration of Helsinki (as revised in South Africa, 1996) and with US regulations. It was approved by the Institutional Review Board of each participating center, and written informed consent was obtained from each participant before enrollment.

Participants
Healthy male or female volunteers were eligible for the study if they were aged 65 years or older, were current smokers (confirmed by positive urine, serum, or plasma cotinine), and had smoked at least 10 cigarettes per day for at least 1 year. Participants were required to weigh no more than 91 kg and to be within 15% of the recommended weight for their age, gender, height, and frame, according to the 1983 Metropolitan Life Assurance Height and Weight Tables. All participants had a normal renal function for their age, that is, creatinine clearance of at least 70 mL/min, as estimated by the method of Cockcroft and Gault.¹⁴ Volunteers with a history of clinically significant medical conditions, conditions affecting drug absorption, or drug or alcohol abuse were excluded from enrollment, as were those with drug allergies or with a supine blood pressure above 165/95 mm Hg on 2 separate occasions or documented electrocardiogram (ECG) abnormalities at the time of screening (in the absence of medication). Participants were required to refrain from taking any investigational drug for at least 4 weeks; concomitant prescription or over-the-counter medications were allowed on a case-by-case basis. Subjects were also required to refrain from strenuous physical activity beginning 72 hours before admission and throughout the study. Participants were not permitted to consume alcohol, methylxanthine-containing products, or grapefruit juice from 48 hours before the first dose to the end of the study. Water was permitted without restriction. There was no restriction on smoking except for study procedures.

Protocol
This was a double-blind, randomized study conducted at 3 centers in the United States (Orlando Clinical Research Center, Orlando, Fla; MDS Pharma Services, Phoenix, Ariz; Clinical Pharmacology Associates, Miami, Fla). Two groups, each consisting of 12 eligible volunteers, were randomized in a 2:1 ratio to receive varenicline or placebo: in group 1 the dose of varenicline was 1 mg once daily for 7 days, whereas in group 2 the dose was 1 mg twice daily on days 1 through 6 with a single dose on day 7. Subjects were screened within 28 days of the first doses. Blinded doses of study medication were prepared by an unblinded member of the clinical research staff, who was not involved in any other aspect of the study; all other study staff were blinded to study medication. Study drug supplies consisted of white, round tablets containing 1 mg varenicline. Placebo was supplied as matching tablets.

Study medication was given with 240 mL water in a fasting state. For morning dosing (7:00 AM), subjects fasted at least 8 hours before and 4 hours after dosing. For evening dosing (7:00 PM) for group 2, subjects fasted at least 3 hours prior to and 2 hours after dosing. Subjects were confined to the Clinical Research Unit (CRU) 24 hours prior to the first dose and remained in the CRU until approximately 48 hours after the day 7 dose. All subjects were dosed under the supervision of the CRU staff. Standardized meals consisting of breakfast, lunch, dinner, and an optional evening snack were served during the inpatient portion of the study. The daily nutritional composition was 50% carbohydrate, 35% fat, and 15% protein.

Sample Collection and Analysis
On day 1, blood samples, sufficient to provide a minimum of 3 mL plasma for the measurement of varenicline concentrations, were obtained by either direct venipuncture or through an indwelling cannula, just prior to dose administration and at 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours after dosing in group 1 and at 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose in group 2. On day 7, further samples were obtained predose and at 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours after the last dose. In addition, samples were obtained predose and 3 hours after the morning dose on days 4, 5, and 6; in group 2, 2 additional samples were drawn on day 4, just prior to and 3 hours after the evening dose.

All blood samples were collected into heparinized tubes and centrifuged at 1700g for 10 minutes at approximately 4°C. Plasma was stored at -20°C or below within 1 hour of collection.

On day 7, a blood sample sufficient to provide at least 10 mL plasma was collected from each subject into an EDTA tube approximately 3 hours after the morning dose (the time of anticipated maximum plasma varenicline concentrations) for the determination of varenicline plasma protein binding.

On days 1 and 7, urine was collected over 0 to 6, 6 to 12, and 12 to 24 hours after dosing in group 1, and over 0 to 6 and 6 to 12 hours in group 2. At the end of each collection period, the total urine volume was recorded, and a 10-mL aliquot from each collection period was stored at -20°C prior to analysis. Plasma, urine, and ultrafiltrate concentrations of varenicline were determined using a validated highperformance liquid chromatography-atmospheric pressure ionization/tandem mass spectrometry assay (LC-API/MS/MS) following liquid-liquid extraction, as described previously¹¹ with the following modification: a guard column (BDS Hypersil Cyano 10 x 2 mm; Thermo Electron Corp, Waltham, Mass) was added to the analytical column. Plasma protein binding of varenicline was determined by ultrafiltration followed by LC-API/MS/MS. For the preparation of ultrafiltrate samples, plasma samples were preincubated at 37°C for about 5 minutes. Aliquots (1 mL) of plasma were then transferred to the filtrate cups of each Amicon Centrifree UF YM-30 device (30 000 mw cutoff; Millipore, Billerica, Mass) and centrifuged at 37°C for 1 hour at 1800g in a fixed angle rotor (IEC model 825/825A; Thermo Electron Corp). The resulting plasma ultrafiltrate was then stored frozen at -20°C prior to analysis. All ultrafiltrate samples were mixed in a 3:7 (volume/volume) ratio with control plasma (ie, 300 µL ultrafiltrate and 700 µL control plasma) for extraction and analysis. The dynamic range of the assay using 1-mL aliquots was 0.100 to 50.0 ng/mL for both plasma and ultrafiltrate, and 1.00 to 500 ng/mL for urine. Plasma varenicline concentrations below the lower limit of quantification (LLOQ = 0.100 ng/mL) were assigned a value of zero for calculation of summary statistics.

Pharmacokinetic Evaluation
Maximum (C_max) and trough (C_min) varenicline concentrations and the time to reach maximum concentrations (t_max) were derived directly from concentration-time plots. The area under the concentration-time curve from zero to the end of the dosing interval (AUC_0-, where = 12 hours for twice-daily dosing or 24 hours for once-daily dosing) was calculated by the linear trapezoidal rule. The apparent elimination rate constant (K_el) on day 7 was calculated by linear least squares regression analysis of the plasma concentration-time data during the terminal log-linear phase. The apparent terminal phase t was calculated as ln(2)/K_el. Renal clearance (CL_R) was calculated by dividing the amount of drug excreted unchanged in urine over a time interval, 12 or 24 hours, by the corresponding AUC_0-.

The attainment of steady-state conditions was assessed by visual inspection of graphical plots of predose concentrations on days 4 through 7 and 24 hours after dosing on day 7, in group 1; in group 2, the 12-hour trough concentrations measured on days 4 and 7 were also included. The observed accumulation factor following repeat dosing was calculated as the ratio of AUC_0- on day 7 to the corresponding AUC_0- value on day 1. The proportion of unbound varenicline in plasma was defined as the concentration of varenicline in ultrafiltrate divided by that in plasma, expressed as a percentage.

All pharmacokinetic calculations were performed using the custom software PK_PARAM2 (internally developed by Pfizer Inc, Groton, Conn). Observed arithmetic means and standard deviations were reported for all pharmacokinetic parameters except t_max values, which were given as median (range).

Safety Assessments
A physical examination and clinical laboratory tests were performed at screening and on day 9: clinical chemistry tests were also performed prior to the first dose of study medication. Serum creatinine was measured on 3 separate occasions (screening, day 0, and day 9). Because the small variation in serum creatinine levels observed throughout the study was not considered an effect of varenicline on renal function but rather reflected the day-to-day variability in creatinine production and elimination,¹⁵ individual creatinine clearances were averaged to estimate the subject's renal function. Vital signs were measured before and 3 hours after morning dosing on days 1 through 7 and 48 hours after morning dosing on day 7. A 12-lead ECG was obtained before the first dose; 3 hours after morning dosing on days 1, 4, and 7; and 48 hours after morning dosing on day 7. Information about adverse events was obtained by nonleading questioning or spontaneous reporting throughout the study.

Statistical Analyses
No specific statistical hypothesis tests were planned. Pharmacokinetic and safety data were summarized through appropriate data tabulations, descriptive statistics, and graphical presentations.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Twenty-four healthy smokers, 17 men and 7 women, aged 65 to 75 years were enrolled, and all completed the study as planned. The demographic characteristics of the participants are summarized in Table I. Varenicline-treated and placebo-treated participants were well matched in terms of demographic characteristics and smoking history.

Varenicline Pharmacokinetics
As shown in Figure 1, varenicline plasma concentrations were higher on day 7 than after a single dose, indicating accumulation of varenicline upon repeat dosing. Table II provides a summary of the relevant pharmacokinetic parameters for varenicline for each dosing regimen and study day. Maximum plasma concentrations of varenicline were achieved within 2 to 3 hours following single or repeat oral administration with each dose regimen. After attaining C_max, individual plasma concentration-time profiles in general declined in a biphasic manner, whereby concentrations of varenicline were detectable in plasma up to 168 hours after repeated administration (Figure 1). On day 7, the elimination phase could be adequately characterized in most subjects, and individual plasma t estimates ranged from 19.0 to 47.6 hours with a mean t of 28.0 hours. Visual inspection of the plasma trough concentration-time profiles suggested that steady-state conditions appeared to develop within 4 days of repeated administration. The steady-state trough plasma levels, C_min, pooled from days 4 to 8 averaged about 3.3 ng/mL after 1-mg once-daily and about 6.0 ng/mL after 1-mg twice-daily dosing. The mean accumulation factor calculated from the ratio of AUC_0- on days 7 and 1 was 2.3 (range, 1.4-2.9) with once-daily dosing and 2.9 (range, 2.5-3.3) with twice-daily dosing. Similarly, C_max values increased, on average 1.8-fold and 2.7-fold, respectively.

View larger version (15K): [in this window] [in a new window]   Figure 1. Mean plasma varenicline concentration-time profiles after single and repeat oral doses of 1 mg varenicline given once or twice daily to healthy elderly smokers.

Mean (±SD) estimates of CL_R for varenicline ranged from 130 ± 45 mL/min to 126 ± 40 mL/min after single oral doses and from 92.1 ± 27.1 mL/min to 130 ± 28 mL/min after repeat dosing (Table II). It was also determined that the percentage of unbound varenicline to plasma proteins ranged from 76% to 97% in this elderly smoking population.

The coefficients of variation (CVs) for C_max and AUC_0- were less than 30% with both dose regimens, indicating that variability in these parameters was in general low. Similarly, CV for the observed C_min values was consistently less than 40% after repeat dosing.

Safety and Tolerability of Varenicline
Adverse events were reported by 4 participants (50%) receiving varenicline 1 mg once daily, 3 (38%) receiving twice-daily treatment, and 5 (62%) in the placebo group (Table III). The most commonly reported adverse event was nausea, which was experienced by 2 subjects in the 1-mg once-daily group, 1 subject in the 1-mg twice-daily group, and 1 subject in the placebo group. All adverse events were mild or moderate in intensity and of these, 67%, 75%, and 57% were considered by the investigator to be treatment related in the varenicline 1-mg once-daily group, varenicline 1-mg twice-daily group, and placebo group, respectively. No participant withdrew from the study because of adverse events. No clinically significant changes in clinical chemistry or the ECG were observed during the study. Mean changes from baseline for supine and standing systolic and diastolic blood pressure and heart rate were similar across the varenicline 1-mg once-daily, varenicline 1-mg twice-daily, and placebo groups, but these did not appear to be treatment related.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
In this trial, the pharmacokinetics, safety, and tolerability of 2 single and multiple oral dose regimens of varenicline were studied for the first time in male and female elderly smokers, aged 65 to 75 years, with normal renal function for their age. The results of this study showed that there was no evidence of concentration- or time-dependent changes in varenicline pharmacokinetics following repeated once- or twice-daily administration for 7 consecutive days. After oral administration of varenicline in elderly smokers, peak plasma concentrations occurred typically within 2 to 3 hours of dosing with both once- and twice-daily dosing. Steady-state conditions were attained within approximately 4 days (which was consistent with the observed overall mean elimination t of about 28 ± 7 hours) and were independent of the dose. Also, once- and twice-daily administrations were associated with an approximate 2-fold and 3-fold increase, respectively, in systemic exposure to varenicline, based on C_max and AUC_0-.

Consistent with excretion data obtained in preclinical animal studies, high amounts of varenicline were recovered in the urine of healthy elderly smokers. The observed renal clearances were similar with both regimens, after single and repeated dosing, thus indicating that the renal elimination of varenicline does not change during repeated administration.

The pharmacokinetic parameters estimated in these elderly smokers were comparable with those obtained in a nonelderly (18-45 years) smoking population.¹⁰ In the latter study, steady-state conditions in younger smokers were attained within 4 days of repeated dosing with 1 mg once-daily varenicline, producing a mean C_max of 7.93 ± 0.90 ng/mL and AUC_0-24 of 144 ± 24 ng·h/mL, and with 1 mg twice-daily varenicline, producing a mean C_max of 10.2 ± 1.0 ng/mL, and an AUC_0-12 of 105 ± 16 ng·h/mL. These results are not unexpected for varenicline, a drug almost exclusively excreted in the urine. Mean creatinine clearance was 78.8 mL/min (range, 63.9-91.6) in the elderly (Table I) and 110 mL/min (range, 78.5-137)¹⁰ in the nonelderly reference population. Because these ranges are overlapping and consistent with normal renal function for the subject's age,¹⁶ renal and total clearances of varenicline, and correspondingly steady-state exposure (AUC_0-), did not change to any appreciable extent between both age populations. In addition, protein binding of varenicline was low in plasma of elderly smokers and comparable (<20%) with that in younger individuals (data on file).

A secondary objective of this study was to evaluate the safety and tolerability of varenicline in this elderly smoking population. It is important to evaluate the tolerability profile of a potential treatment for smoking cessation, particularly in the elderly population, because the normal physiologic processes associated with aging can have diverse effects on drug pharmacokinetics and pharmacodynamics.¹⁷ These age-related changes frequently affect drugs acting on the central nervous system and, thus, are particularly relevant to drugs intended for use in smoking cessation. The results of this study showed that varenicline 1 mg once- or twice-daily is well tolerated in elderly persons with normal renal function; there were no overall differences in adverse events or safety parameters observed versus placebo. The most common adverse event reported across treatment groups was nausea (13%-25%); the majority (50%-75%) of the adverse events recorded were considered by the investigator to be treatment related. All of the adverse events were mild to moderate in intensity, and no participants withdrew from the study because of adverse events. The observed tolerability of varenicline may reflect its unique mechanism of action and pharmacokinetic profile. Varenicline binds selectively with high affinity to 4ß2 receptors and has little affinity for other nicotinic receptor subtypes or other receptor populations.¹⁸

In conclusion, this study has shown that the pharmacokinetic disposition of varenicline in elderly smokers with normal renal function is similar to that in younger, healthy persons and that varenicline was well tolerated in this population. No dose adjustment based solely on age is considered necessary.

	ACKNOWLEDGEMENTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The authors thank Al Calcagni for coordination of varenicline sample analysis and Rebecca Madura for clinical study management support.

Financial disclosure: This study was funded by Pfizer Inc. Aaron H. Burstein, Terence Fullerton, David J. Clark, and Hélène M. Faessel are employees of Pfizer Global Research and Developement.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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8. Tapper AR, McKinney SL, Nashmi R, et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nicotine activation of alpha4^* receptors: sufficient for reward, tolerance, and sensitization. Science. 2004;306: 1029-1032.[Abstract/Free Full Text]

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10. Faessel HM, Gibbs MA, Clark DJ, Morse TA, Burstein AH. Multiple dose pharmacokinetics and pharmacodynamics of the nicotinic receptor partial agonist, varenicline, in healthy smokers. J Clin Pharmacol. In press.

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13. Oncken C, Watsky E, Reeves K, Anziano R, and the Varenicline Study Working Group. Efficacy and safety of the novel selective nicotinic receptor partial agonist varenicline for smoking cessation. J Am Coll Cardiol. 2005;45(suppl A): 381A.

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15. Matzke GR, Millikin SP. Influence of renal function and dialysis on drug disposition. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetic: Principles of Therapeutic Drug Monitoring. 3rd ed. Vancouver, Wash: Applied Therapeutics Inc; 1992: 1-49.

16. Davies DF, Shock NW. Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest. 1950;29: 496-507.[Web of Science][Medline] [Order article via Infotrieve]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Burstein, A. H. Articles by Faessel, H. M. Search for Related Content PubMed PubMed Citation Articles by Burstein, A. H. Articles by Faessel, H. M. Social Bookmarking                   What's this?