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Aaron H Burstein - One of the best experts on this subject based on the ideXlab platform.
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A Review of the Clinical Pharmacokinetics and Pharmacodynamics of Varenicline for Smoking Cessation
Clinical Pharmacokinetics, 2010Co-Authors: Helene M Faessel, Hans Rollema, R. Scott Obach, Patanjali Ravva, Kathryn E. Williams, Aaron H BursteinAbstract:Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α_4β_2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of Varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of Varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of Varenicline. In vitro , Varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when Varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of Varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to Varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on Varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that Varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing Varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in Varenicline clinical trials, with an incidence that was sexrelated and increased with Varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of Varenicline simplify its use in clinical practice.
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A Review of the Clinical Pharmacokinetics and Pharmacodynamics of Varenicline for Smoking Cessation
Clinical Pharmacokinetics, 2010Co-Authors: Helene M Faessel, Hans Rollema, R. Scott Obach, Patanjali Ravva, Kathryn E. Williams, Aaron H BursteinAbstract:Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α_4β_2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of Varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of Varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of Varenicline. In vitro , Varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when Varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of Varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to Varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on Varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that Varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing Varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in Varenicline clinical trials, with an incidence that was sexrelated and increased with Varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of Varenicline simplify its use in clinical practice.
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a review of the clinical pharmacokinetics and pharmacodynamics of Varenicline for smoking cessation
Clinical Pharmacokinectics, 2010Co-Authors: Helene M Faessel, Hans Rollema, Patanjali Ravva, Kathryn E. Williams, Scott R Obach, Aaron H BursteinAbstract:Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α4β2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of Varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of Varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of Varenicline. In vitro, Varenicline does not inhibit nor induce the activity of the major CYP enzymes.
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multiple dose pharmacokinetics of the selective nicotinic receptor partial agonist Varenicline in healthy smokers
The Journal of Clinical Pharmacology, 2006Co-Authors: Helene M Faessel, Megan A Gibbs, David J Clark, Kevin Rohrbacher, Marilyn Stolar, Aaron H BursteinAbstract:Varenicline is a novel and selective α4β2 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.
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single dose pharmacokinetics of Varenicline a selective nicotinic receptor partial agonist in healthy smokers and nonsmokers
The Journal of Clinical Pharmacology, 2006Co-Authors: Helene M Faessel, Megan A Gibbs, David J Clark, Bill J Smith, Jason S Gobey, Aaron H BursteinAbstract:Varenicline is a novel and selective alpha4beta2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double-blind, placebo-controlled, single-dose, dose-escalation study were to determine the clinical pharmacology of single doses of Varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of Varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to Varenicline and 2 subjects to placebo. Subjects received one single oral administration of Varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to Varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time-of-day dosing did not affect the pharmacokinetics of Varenicline.
Helene M Faessel - One of the best experts on this subject based on the ideXlab platform.
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A Review of the Clinical Pharmacokinetics and Pharmacodynamics of Varenicline for Smoking Cessation
Clinical Pharmacokinetics, 2010Co-Authors: Helene M Faessel, Hans Rollema, R. Scott Obach, Patanjali Ravva, Kathryn E. Williams, Aaron H BursteinAbstract:Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α_4β_2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of Varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of Varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of Varenicline. In vitro , Varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when Varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of Varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to Varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on Varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that Varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing Varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in Varenicline clinical trials, with an incidence that was sexrelated and increased with Varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of Varenicline simplify its use in clinical practice.
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A Review of the Clinical Pharmacokinetics and Pharmacodynamics of Varenicline for Smoking Cessation
Clinical Pharmacokinetics, 2010Co-Authors: Helene M Faessel, Hans Rollema, R. Scott Obach, Patanjali Ravva, Kathryn E. Williams, Aaron H BursteinAbstract:Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α_4β_2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of Varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of Varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of Varenicline. In vitro , Varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when Varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of Varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to Varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on Varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that Varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing Varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in Varenicline clinical trials, with an incidence that was sexrelated and increased with Varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of Varenicline simplify its use in clinical practice.
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a review of the clinical pharmacokinetics and pharmacodynamics of Varenicline for smoking cessation
Clinical Pharmacokinectics, 2010Co-Authors: Helene M Faessel, Hans Rollema, Patanjali Ravva, Kathryn E. Williams, Scott R Obach, Aaron H BursteinAbstract:Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α4β2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of Varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of Varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of Varenicline. In vitro, Varenicline does not inhibit nor induce the activity of the major CYP enzymes.
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multiple dose pharmacokinetics of the selective nicotinic receptor partial agonist Varenicline in healthy smokers
The Journal of Clinical Pharmacology, 2006Co-Authors: Helene M Faessel, Megan A Gibbs, David J Clark, Kevin Rohrbacher, Marilyn Stolar, Aaron H BursteinAbstract:Varenicline is a novel and selective α4β2 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.
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single dose pharmacokinetics of Varenicline a selective nicotinic receptor partial agonist in healthy smokers and nonsmokers
The Journal of Clinical Pharmacology, 2006Co-Authors: Helene M Faessel, Megan A Gibbs, David J Clark, Bill J Smith, Jason S Gobey, Aaron H BursteinAbstract:Varenicline is a novel and selective alpha4beta2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double-blind, placebo-controlled, single-dose, dose-escalation study were to determine the clinical pharmacology of single doses of Varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of Varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to Varenicline and 2 subjects to placebo. Subjects received one single oral administration of Varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to Varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time-of-day dosing did not affect the pharmacokinetics of Varenicline.
Robert A. Schnoll - One of the best experts on this subject based on the ideXlab platform.
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medication adherence and rate of nicotine metabolism are associated with response to treatment with Varenicline among smokers with hiv
Addictive Behaviors, 2021Co-Authors: Anna Marika Bauer, Frank T. Leone, Brian Hitsman, Mackenzie Hosie Quinn, Su Fen Lubitz, Alex Flitter, Rebecca L Ashare, Robert E Gross, Robert A. SchnollAbstract:Abstract Introduction PLWHA who smoke have shown lower cessation rates within placebo-controlled randomized trials of Varenicline. Adherence and rate of nicotine metabolism may be associated with quit rates in such clinical trials. Methods This secondary analysis of a randomized placebo-controlled trial of Varenicline for smoking among PLWHA (N=179) examined the relationship between Varenicline adherence (pill count, ≥80% of pills), nicotine metabolism (based on the nicotine metabolite ratio; NMR) and end-of-treatment smoking cessation (self-reported 7-day point prevalence abstinence, confirmed with carbon monoxide of ≤ 8ppm, at the end of treatment; EOT). Results Combining Varenicline and placebo arms, greater adherence (OR=1.011, 95% CI:1.00-1.02, p=0.051) and faster nicotine metabolism (OR=3.08, 95% CI:1.01-9.37, p=0.047) were related to higher quit rates. In separate models, adherence (OR=1.009, 95% CI:1.004-1.01, p Conclusions Increasing Varenicline adherence and ensuring that fast nicotine metabolizers receive Varenicline may increase quit rates for PLWHA.
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The association between self-reported Varenicline adherence and Varenicline blood levels in a sample of cancer patients receiving treatment for tobacco dependence.
Addictive behaviors reports, 2018Co-Authors: Grace Crawford, Nancy C. Jao, Annie R. Peng, Frank T. Leone, Ravi Kalhan, Rachel F. Tyndale, Jessica Weisbrot, Brian Hitsman, Robert A. SchnollAbstract:Introduction The degree to which smokers quit successfully with Varenicline is strongly associated with their adherence to the medication regimen. Thus, measuring Varenicline adherence to identify smokers needing additional intervention is a priority. Few studies, however, have examined the validity of self-reported Varenicline adherence, using a biological assessment of adherence as a reference. No study has examined this issue among cancer patients trying to quit smoking, who may show unique patterns of adherence given their medical comorbidity. Methods This study used data from 76 cancer patients who received Varenicline and provided self-reported Varenicline adherence data (pill count) and a blood sample to determine Varenicline metabolites 4 weeks after initiating Varenicline. Results Receiver operating characteristic (ROC) curve analyses of plasma Varenicline levels showed that 4 ng/ml was the optimal cut-point for differentiating adherence with significant (p's
Tony P George - One of the best experts on this subject based on the ideXlab platform.
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Varenicline for smoking cessation in bipolar disorder a randomized double blind placebo controlled study
The Journal of Clinical Psychiatry, 2014Co-Authors: K Roy N Chengappa, Kenneth A Perkins, Jaspreet S Brar, Patricia J Schlicht, Scott R Turkin, Michelle L Hetrick, Michele D Levine, Tony P GeorgeAbstract:OBJECTIVE Virtually no clinical trials for smoking cessation have been undertaken in bipolar disorder. Varenicline has shown efficacy for smoking cessation, but warnings about neuropsychiatric adverse events have been issued. We assessed the efficacy and safety of Varenicline in euthymic bipolar subjects motivated to quit smoking. METHOD Clinically stable adult patients with DSM-IV bipolar disorder (n = 60) who smoked ≥ 10 cigarettes per day were randomized to a 3-month, double-blind, placebo-controlled Varenicline trial and a 3-month follow-up. Study enrollment was completed from February 2010 through March 2013. Varenicline was dosed using standard titration, and smoking cessation counseling was provided to all patients. The primary outcome was defined as a 7-day point prevalence of self-reported no smoking verified by expired carbon monoxide level < 10 ppm at 12 weeks. Psychopathology and side-effects were assessed at each visit. RESULTS At 3 months (end of treatment), significantly more subjects quit smoking with Varenicline (n/n = 15/31, 48.4%) than with placebo (n/n = 3/29, 10.3%) (OR = 8.1; 95% CI, 2.03-32.5; P < .002). At 6 months, 6 of 31 Varenicline-treated subjects (19.4%) remained abstinent compared to 2 of 29 (6.90%) assigned to placebo (OR = 3.2; 95% CI, 0.60-17.6; P = .17). Psychopathology scores remained stable. Ten serious adverse events occurred (n = 6, Varenicline; n = 4, placebo). Abnormal dreams occurred significantly more often in Varenicline-treated subjects (n/n = 18/31, 61.3%) than in those receiving placebo (n/n = 9/29, 31%; Fisher exact test, P = .04). Eight Varenicline-treated and 5 placebo-assigned subjects expressed fleeting suicidal ideation, a nonsignificant difference. CONCLUSIONS Varenicline shows efficacy for initiating smoking cessation in bipolar patients, but medication trials of longer duration are warranted for maintaining abstinence. Vigilance for neuropsychiatric adverse events is prudent when initiating Varenicline for smoking cessation in this patient population. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01010204.
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a randomized double blind placebo controlled study evaluating the safety and efficacy of Varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder
The Journal of Clinical Psychiatry, 2012Co-Authors: Jill M Williams, Robert M Anthenelli, Chad D Morris, Joan Treadow, John R Thompson, Carla Yunis, Tony P GeorgeAbstract:Objective Effective smoking cessation treatments are needed for patients with schizophrenia, who, compared with the general population, have high rates of cigarette smoking and more difficulty quitting. We evaluated the safety and efficacy of Varenicline for smoking cessation in outpatients with stable schizophrenia or schizoaffective disorder. Method In this 12-week, randomized, double-blind, multicenter trial (May 8, 2008, to April 1, 2010), 127 smokers (≥ 15 cigarettes/d) with DSM-IV-confirmed schizophrenia or schizoaffective disorder received Varenicline or placebo (2:1 ratio). The primary outcome was safety and tolerability of Varenicline assessed by adverse events frequency and changes in ratings on the Positive and Negative Syndrome Scale and other psychiatric scales from baseline to 24 weeks. Abstinence was defined as no smoking 7 days prior to weeks 12 and 24, verified by carbon monoxide level. Results Eighty-four participants received Varenicline; 43, placebo. At 12 weeks (end of treatment), 16/84 Varenicline-treated patients (19.0%) met smoking cessation criteria versus 2/43 (4.7%) for placebo (P = .046). At 24 weeks, 10/84 (11.9%) Varenicline-treated and 1/43 (2.3%) placebo-treated patients, respectively, met abstinence criteria (P = .090). Total adverse event rates were similar between groups, with no significant changes in symptoms of schizophrenia or in mood and anxiety ratings. Rates of suicidal ideation adverse events were 6.0% (Varenicline) and 7.0% (placebo) (P = 1.0). There was 1 suicide attempt by a Varenicline patient with a lifetime history of similar attempts and no completed suicides. Conclusions Varenicline was well tolerated, with no evidence of exacerbation of symptoms, and was associated with significantly higher smoking cessation rates versus placebo at 12 weeks. Our findings suggest Varenicline is a suitable smoking cessation therapy for patients with schizophrenia or schizoaffective disorder. Trial registration ClinicalTrials.gov identifier: NCT00644969.
Hans Rollema - One of the best experts on this subject based on the ideXlab platform.
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Varenicline: mode of action, efficacy, safety and accumulated experience salient for clinical populations
Current Medical Research and Opinion, 2020Co-Authors: Serena Tonstad, Hans Rollema, Ivan Berlin, Peter Hajek, Thomas Mcrae, Karl Fagerström, Cynthia Arons, Charl Els, Cristina RussAbstract:Objective: Varenicline, a selective partial agonist of the α4β2 nicotinic acetylcholine receptor, is a smoking cessation pharmacotherapy that more than doubles the chance of quitting smoking at 6 months compared with placebo. This article reviews salient knowledge of the discovery, pharmacological characteristics, and the efficacy and safety of Varenicline in general and in specific populations of smokers and provides recommendations to support use in clinical practice. Methods: Literature searches for Varenicline were conducted using PubMed, with date limitations of 2000-2018 inclusive, using search terms covering the discovery, mechanism of action, pharmacokinetics, efficacy and safety in different populations of smokers, alternative quit approaches and combination therapy. Selection of safety and efficacy data was limited to clinical trials, meta-analyses and observational studies. Results: Standard administration of Varenicline is efficacious in helping smokers to quit, including smokers with cardiovascular disease and chronic obstructive pulmonary disease. Furthermore, Varenicline efficacy may be improved with pre-loading, a gradual quitting approach for smokers unwilling or unable to quit abruptly, and extended treatment in smokers who have recently quit to help maintain abstinence. Initial concerns regarding the association of Varenicline with increased risk of neuropsychiatric and cardiovascular adverse events have been disproven after extensive clinical evaluations, and the benefit-risk profile of Varenicline is considered favorable. Conclusions: Varenicline is efficacious and safe for all adult smokers with a range of clinical characteristics. Evidence suggests that approaches offering greater flexibility in timing and duration of treatment may further extend treatment efficacy and clinical reach.
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A Review of the Clinical Pharmacokinetics and Pharmacodynamics of Varenicline for Smoking Cessation
Clinical Pharmacokinetics, 2010Co-Authors: Helene M Faessel, Hans Rollema, R. Scott Obach, Patanjali Ravva, Kathryn E. Williams, Aaron H BursteinAbstract:Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α_4β_2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of Varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of Varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of Varenicline. In vitro , Varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when Varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of Varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to Varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on Varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that Varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing Varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in Varenicline clinical trials, with an incidence that was sexrelated and increased with Varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of Varenicline simplify its use in clinical practice.
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A Review of the Clinical Pharmacokinetics and Pharmacodynamics of Varenicline for Smoking Cessation
Clinical Pharmacokinetics, 2010Co-Authors: Helene M Faessel, Hans Rollema, R. Scott Obach, Patanjali Ravva, Kathryn E. Williams, Aaron H BursteinAbstract:Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α_4β_2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of Varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of Varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of Varenicline. In vitro , Varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when Varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of Varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to Varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on Varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that Varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing Varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in Varenicline clinical trials, with an incidence that was sexrelated and increased with Varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of Varenicline simplify its use in clinical practice.
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a review of the clinical pharmacokinetics and pharmacodynamics of Varenicline for smoking cessation
Clinical Pharmacokinectics, 2010Co-Authors: Helene M Faessel, Hans Rollema, Patanjali Ravva, Kathryn E. Williams, Scott R Obach, Aaron H BursteinAbstract:Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α4β2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of Varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of Varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of Varenicline. In vitro, Varenicline does not inhibit nor induce the activity of the major CYP enzymes.
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The α4β2 nicotinic acetylcholine-receptor partial agonist Varenicline inhibits both nicotine self-administration following repeated dosing and reinstatement of nicotine seeking in rats
Psychopharmacology, 2010Co-Authors: Eoin C. O’connor, Hans Rollema, Dale Parker, Andy N. MeadAbstract:Introduction The α4β2 nicotinic acetylcholine receptor partial agonist Varenicline has greater efficacy than other pharmacotherapeutic aids for smoking cessation. This presents an opportunity to evaluate the predictive validity of rat models of nicotine taking and relapse. The aim of this study was to evaluate the ability of Varenicline to attenuate nicotine self-administration and relapse, as modelled by the reinstatement model of nicotine relapse in rats. Materials and methods Rats were trained to respond for intravenous nicotine under a fixed ratio schedule of reinforcement. The effects of Varenicline (0.3–3.0 mg/kg s.c.) on both nicotine and food self-administration and reinstatement of nicotine seeking were evaluated. Results and discussion Varenicline dose-dependently reduced nicotine self-administration and attenuated both nicotine prime and combined nicotine prime plus nicotine-paired cue-induced reinstatement. Varenicline had no effect on cue-induced reinstatement in the absence of a nicotine prime nor did it induce reinstatement when given alone. Conclusion The effects of Varenicline on nicotine-induced reinstatement of drug-seeking are consistent with the demonstrated clinical efficacy of Varenicline for smoking cessation.
