Kathryn E. Williams

Varenicline versus transdermal nicotine patch for smoking cessation: Results from a randomised, open-label trial

Background: Varenicline, a new treatment for smoking cessation, has demonstrated significantly greater efficacy over placebo and sustained release bupropion (bupropion SR). A study was undertaken to compare a 12-week standard regimen of varenicline with a 10-week standard regimen of transdermal nicotine replacement therapy (NRT) for smoking cessation. Methods: In this 52-week, open-label, randomised, multicentre, phase 3 trial conducted in Belgium, France, the Netherlands, UK and USA, participants were randomly assigned (1:1) to receive varenicline uptitrated to 1 mg twice daily for 12 weeks or transdermal NRT (21 mg/day reducing to 7 mg/day) for 10 weeks. Non-treatment follow-up continued to week 52. The primary outcome was the biochemically confirmed (exhaled carbon monoxide ⩽10 ppm) self-reported continuous abstinence rate (CAR) for the last 4 weeks of the treatment period in participants who had taken at least one dose of treatment. Secondary outcomes included CAR from the last 4 weeks of treatment through weeks 24 and 52, and measures of craving, withdrawal and smoking satisfaction. Results: A total of 376 and 370 participants assigned to varenicline and NRT, respectively, were eligible for analysis. The CAR for the last 4 weeks of treatment was significantly greater for varenicline (55.9%) than NRT (43.2%; OR 1.70, 95% CI 1.26 to 2.28, p<0.001). The week 52 CAR (NRT, weeks 8–52; varenicline, weeks 9–52) was 26.1% for varenicline and 20.3% for NRT (OR 1.40, 95% CI 0.99 to 1.99, p = 0.056). Varenicline significantly reduced craving (p<0.001), withdrawal symptoms (p<0.001) and smoking satisfaction (p<0.001) compared with NRT. The most frequent adverse event was nausea (varenicline, 37.2%; NRT, 9.7%). Conclusions: The outcomes of this trial established that abstinence from smoking was greater and craving, withdrawal symptoms and smoking satisfaction were less at the end of treatment with varenicline than with transdermal NRT. Trial registration number: NCT00143325.

Weight effects associated with antipsychotics: A comprehensive database analysis

BACKGROUND Available data on atypical antipsychotic-induced weight gain are limited by a number of methodological factors. The objective of this report is to evaluate short-term (N=1742) and long-term (N=1649) weight effects in patients receiving standard doses of amisulpride, haloperidol, olanzapine, risperidone, ziprasidone, and placebo based on 21 randomized, placebo-controlled, parallel-group studies from an integrated clinical trial database. METHOD Analyses of the integrated ziprasidone schizophrenia trials database were performed to estimate the weighted average of weight change and the percentage of subjects experiencing weight gain (or weight loss) across studies for each agent studied, based on fixed- and random-effects models. Durations of treatment exposure in long-term trials were controlled by well-defined time windows (6 month: 150 to 210 days; 1 year: 330 to 390 days). Weight gain or loss was defined using a 7% change from baseline threshold. RESULTS During long-term therapy with 1-year treatment duration, incidence of weight gain for subjects treated with ziprasidone (17%) was not significantly different from the placebo (13%) or haloperidol (41%) groups based on 95% confidence interval. In contrast, significantly greater weight gain incidence was observed for the olanzapine (57%) and risperidone (39%) groups compared to placebo. Median weight change of +0.49, -0.18, +1.50 and +0.55 lb/month was observed for haloperidol, ziprasidone, olanzapine and risperidone subjects, respectively, indicating differential weight change patterns compared to placebo (-0.32). Similar results were observed for the short-term (4-12 weeks) and 6-month treatment exposure cohorts. CONCLUSIONS Our results confirm significant differences in long-term weight effects among atypical antipsychotics, consistent with findings from prior meta-analysis of antipsychotic-induced weight gain [Allison, D.B., Mentore, J.L., Heo, M., Chandler, L.P., Capelleri, J.C., Infante, M.C., Weiden, P.J., 1999. Antipsychotic induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156, 1686-1696] and the CATIE schizophrenia study [Lieberman, J.A., Stroup, T.S., McEvoy, J.P., et al., 2005. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353, 1209-1223].

A double-blind study evaluating the long-term safety of varenicline for smoking cessation

ABSTRACT Objective: We assessed the safety of long-term varenicline administration for smoking cessation. Methods: In this randomized, double-blind, multicenter trial, eligible adult smokers (18–75 years) who smoked an average of ≥10 cigarettes/day were randomized to either varenicline 1 mg twice daily (BID) or placebo for 52 weeks. Subjects made weekly clinic visits until week 8, and then every 4 weeks until week 52, with a follow-up visit at week 53. The target quit date was the morning of the week 1 clinic visit. Brief counseling was provided at each visit, and vital signs, adverse events (AEs), and smoking status were documented. Other laboratory measures were collected at specified visits. Results: A total of 251 subjects were randomized to varenicline and 126 to placebo. Approximately half of the subjects in each arm completed the study (53.8% varenicline; 46.8% placebo). Treatment-emergent AEs were observed in 96.4% of varenicline- and 82.5% of placebo-treated subjects during the study. Common varenicline-associated AEs were nausea (40.2%), abnormal dreams (22.7%), and insomnia (19.1%). Most AEs were considered mild or moderate in intensity. AEs leading to discontinuation of varenicline treatment included nausea (7.6%), insomnia (3.2%), and abnormal dreams (2.4%). A single varenicline-related serious AE, bilateral subcapsular cataracts, was observed. At week 52, 7-day point prevalence abstinence rates were 36.7% (varenicline) and 7.9% (placebo). Conclusions: Varenicline 1 mg BID can be safely administered for up to 1 year. Varenicline was also a more effective smoking cessation aid than placebo throughout the study, supporting both its short- (12-week) and long-term (52-week) efficacy. Trial registration: ClinicalTrials.gov identifier: NCT00143299.

Preclinical pharmacology of the α4β2 nAChR partial agonist varenicline related to effects on reward, mood and cognition

The pharmacological properties and pharmacokinetic profile of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline provide an advantageous combination of free brain levels and functional potencies at the target receptor that for a large part explain its efficacy as a smoking cessation aid. Since alpha4beta2 and other nAChR subtypes play important roles in mediating central processes that control reward, mood, cognition and attention, there is interest in examining the effects of selective nAChR ligands such as varenicline in preclinical animal models that assess these behaviors. Here we describe results from studies on vareniclines effects in animal models of addiction, depression, cognition and attention and discuss these in the context of recently published preclinical and preliminary clinical studies that collected data on vareniclines effects on mood, cognition and alcohol abuse disorder. Taken together, the preclinical and the limited clinical data show beneficial effects of varenicline, but further clinical studies are needed to evaluate whether the preclinical effects observed in animal models are translatable to the clinic.

The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers: a randomized controlled trial.

ABSTRACT Objective: To determine whether self-regulated flexible dosing with varenicline tartrate is safe and effective for smoking cessation. Research design and methods: 320 healthy, motivated-to-quit smokers (≥10 cigarettes/day) aged 18–65 years, entered a multicenter, randomized, double-blind, placebo-controlled study – conducted between December 26, 2001 and June 24, 2003 – with a 12-week treatment phase and 40-week, double-blind, non-treatment follow-up. Treatment consisted of varenicline or placebo in fixed doses (Week 1: titrated from 0.5 to 1.0 mg/day) followed by a self-regulated flexible schedule (Weeks 2–12: 0.5–2.0 mg/day). Main outcome measures: Primary outcomes included carbon monoxide-confirmed continuous abstinence rate (CAR) from smoking for Weeks 4 through 7, 9 through 12, and 9 through 52. Secondary outcomes included CAR from Weeks 9 through 24, 7-day point prevalence of abstinence, safety assessments, and measures of craving, withdrawal, and smoking reward. Results: Superior CARs were observed in varenicline-treated (n = 157) versus placebo participants (n = 155) for Weeks 4 through 7 (38.2 vs. 11.6%), 9 through 12 (40.1 vs. 11.6%), 9 through 24 (28.0 vs. 9.0%), and 9 through 52 (22.3 vs. 7.7%) (all p < 0.001). Seven-day point prevalence was higher in varenicline-treated than placebo participants at Weeks 12 (46.5 vs. 14.2%; p < 0.001), 24 (32.5 vs. 13.5%; p < 0.001), and 52 (28.0 vs. 13.5%; p = 0.001). Overall, medication compliance was high, although varenicline-treated, but not placebo, participants tended to taper down their dosage over time. Total treatment-emergent AEs were 77.1% (varenicline: 121/157) and 65.8% (placebo: 102/155). Few AEs led to treatment discontinuation (varenicline: 11/157, 7.0% and placebo: 7/155, 4.5%). Participants were primarily healthy Caucasians, so more research is necessary to determine how applicable these findings are to other populations. Conclusions: A self-regulated, flexible dosing regimen of varenicline is well tolerated, with superior effectiveness versus placebo for smoking cessation. Trial registration: ClinicalTrials.gov identifier: NCT00150228.

A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation.

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.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.

Pharmacokinetics, safety, and tolerability of varenicline in healthy adolescent smokers: A multicenter, randomized, double-blind, placebo-controlled, parallel-group study

BACKGROUND Varenicline is approved as an aid to smoking cessation in adults aged > or =18 years. OBJECTIVE The goal of this study was to characterize the multiple-dose pharmacokinetics, safety, and tolerability of varenicline in adolescent smokers. METHODS This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled healthy 12- to 16-year-old smokers (> or =3 cigarettes daily) into high-body-weight (>55 kg) and low-body-weight (< or =55 kg) groups. Subjects were randomized to receive 14 days of treatment with a high dose of varenicline, a low dose of varenicline, or placebo. The varenicline doses in the high-body-weight group were 1 mg BID and 0.5 mg BID; the varenicline doses in the low-body-weight group were 0.5 mg BID and 0.5 mg once daily. The apparent renal clearance (CL/F) and volume of distribution (V/F) of varenicline and the effect of body weight on these parameters were estimated using nonlinear mixed-effects modeling. RESULTS The high-body-weight group consisted of 35 subjects (65.7% male; 77.1% white; mean age, 15.2 years). The low-body-weight group consisted of 37 subjects (37.8% male; 48.6% white; mean age, 14.3 years). The pharmacokinetic parameters of varenicline were dose proportional over the dose range from 0.5 to 2 mg/d. The CL/F for a 70-kg adolescent was 10.4 L/h, comparable to that in a 70-kg adult. The estimated varenicline V/F was decreased in individuals of small body size, thus predicting a varenicline C(max) approximately 30% greater in low-body-weight subjects than in high-body-weight subjects. In high-body-weight subjects, steady-state varenicline exposure, as represented by the AUC(0-24), was 197.0 ng . h/mL for varenicline 1 mg BID and 95.7 ng . h/mL for varenicline 0.5 mg BID, consistent with values reported previously in adult smokers at the equivalent doses. In low-body-weight subjects, varenicline exposure was 126.3 ng . h/mL for varenicline 0.5 mg BID and 60.1 ng . h/mL for varenicline 0.5 mg once daily, values at the lower end of the range observed previously in adults at doses of 1 mg BID and 0.5 mg BID, respectively. Among high-body-weight subjects, adverse events (AEs) were reported by 57.1% of subjects in both the high- and low-dose varenicline groups and by 14.3% of subjects in the placebo group; among low-body-weight subjects, AEs were reported by 64.3%, 73.3%, and 12.5% of subjects in the high-dose varenicline, low-dose varenicline, and placebo groups, respectively. The most common AEs were nausea, headache, vomiting, and dizziness. Psychiatric AEs that were considered treatment related included abnormal dreams in 2 subjects and mild, transient anger in 1 subject. Of the AEs reported by > or =1 subject in any treatment group, > or =92% were mild in intensity. No subject discontinued the study because of an AE. CONCLUSIONS Varenicline steady-state exposure in study subjects weighing >55 kg was similar to that observed previously in adults. The body-weight effect on varenicline pharmacokinetics, which resulted in higher exposure in individuals of smaller body size (< or =55 kg), was adequately offset by administration of half the varenicline dose recommended in adults. Varenicline was generally well tolerated during the 14-day treatment period. Clinical Trials Identification Number: NCT00463918.

Varenicline overdose in a teenager - a clinical pharmacology perspective

We comment here on the case report of varenicline overdosing in a teenager who ingested 30 tablets of 0.5 mg varenicline without serious adverse events and was dismissed from the hospital 8 h after admission. Data from phase 1 clinical trials showed rapid vomiting responses after high doses of varenicline. Maximum plasma concentrations after a single 10-mg dose, at which all subjects vomited, were found to range from 4.1 to 18 ng/mL, similar to those observed after a single 3-mg dose. Dose-escalating studies have consistently led to permanent discontinuation of subjects because of high incidence of early onset of vomiting. Analyses of plasma peak exposures observed following multiple days of high-dose regimens of up to 3 mg daily indicated that circulating concentrations never exceeded 28.3 ng/mL in any individual. In this overdose case, it is reasonable to expect that after acute ingestion of a single 15-mg dose, the systemic exposure of varenicline would be considerably reduced following emesis, reaching levels near those observed in healthy volunteers administered 10 mg. The highest concentration observed after a 10-mg dose, 18 ng/mL, corresponds to free levels of varenicline of approximately 70 nM that are available for interactions with the target and other receptors. At that concentration, varenicline maintains good α4β2 selectivity and is unlikely to cause nicotine-like toxicity, because it has much higher affinity for α4β2 nAChRs (Ki=0.15 nM) than for other nAChRs (Ki>86 nM) or transmitter receptors and transporters (Ki>350 nM) and lacks affinity for muscle-type α1β1δγε nAChRs (Ki>10 μM) and smooth muscle-type muscarinic AChRs (Ki>3 μM). The transient increases in blood pressure and heart rate that were described in the overdose case could be a consequence of the powerful autonomic response associated with vomiting. One possible mechanism of vomiting induced by high varenicline doses is activation of gastrointestinal 5-HT3 receptors. As varenicline is a 5-HT3A receptor agonist (EC50=1 μM), it is conceivable that immediately after ingesting high doses, gut concentrations could be high enough to allow transient activation of local 5-HT3 receptors. This mechanism would explain a rapid onset vomiting response that effectively limits systemic exposure. In summary, the most frequent adverse events of varenicline, nausea and at high doses vomiting, can act as a protection mechanism that reduces risk of overexposure when patients either accidentally or intentionally overdose.