Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Varenicline on Nicotine Craving in Adult Smokers

Ravva, Patanjali; Gastonguay, Marc R.; Faessel, Hélène M.; Lee, Theodore C.; Niaura, Raymond

doi:10.1093/ntr/ntu154

Cited by 14 publications

(15 citation statements)

References 35 publications

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“…Similarly, levels greater than 5 ng/ml plasma varenicline were associated with reduced rates of heavy drinking, though only 8 participants achieved plasma varenicline levels of ≥ 5. This is consistent with findings indicating that 2 mg/day varenicline decreased nicotine craving in smokers, and that this response was related to increased plasma varenicline levels (Ravva et al, 2015), although the pharmacokinetic data were also highly variable in that study. Together, our exploratory findings suggest that plasma varenicline levels may need to be greater than 5 ng/ml to be efficacious in reducing consumption in heavy drinkers.…”

Section: Discussionsupporting

confidence: 91%

“…However, few studies have examined the relationship between plasma varenicline levels and drug-related outcomes. In a recent investigation on pharmacokinetic modeling of varenicline on nicotine craving, 2 mg/day varenicline decreased craving and the magnitude of this response was related to higher plasma varenicline levels in smokers, though this response was highly variable (Ravva et al, 2015). To date, there are no studies examining the relationship between plasma varenicline levels and drinking behavior.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Lowering the Dose of Varenicline on Alcohol Self-administration in Drinkers With Alcohol Use Disorders

Verplaetse

Pittman

Shi

et al. 2016

Journal of Addiction Medicine

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Objectives Varenicline (2mg/day) has been shown to be efficacious in reducing alcohol consumption. A lower dose of varenicline may be effective in reducing alcohol use while minimizing the potential for side effects. Methods This double-blind, placebo-controlled investigation examined the effect of varenicline (0, 1, 2 mg/day) on alcohol consumption in non-treatment seeking adults meeting DSM-IV criteria for alcohol use disorders (n = 60). Following 7-days of medication pretreatment, participants were administered a low fixed dose of alcohol (0.3 g/dL), and subjective and physiologic responses were assessed. A 2-hour ad-libitum alcohol self-administration period followed. We also explored relationships between plasma varenicline levels and consumption. Results Overall, frequency and severity of adverse events were minimal. The 1mg/day dose reduced the frequency of insomnia compared to the 2mg/day dose. The 2 mg/day varenicline dose versus placebo reduced alcohol craving and showed limited effect on reduced alcohol consumption. Alcohol craving and consumption did not differ between the 1 mg/day varenicline dose versus placebo. Trough varenicline plasma levels ≥ 3 ng/ml were associated with reduced drinking and levels ≥ 5ng/ml were associated with reduced heavy drinking. Conclusions Overall, we found no evidence supporting an effect of 1 mg/day varenicline on craving or consumption, suggesting that doses of varenicline less than 2mg/day may not be effective in reducing alcohol-related outcomes. Importantly, results suggest that higher plasma levels of varenicline may be needed in order to maximize the effect of varenicline on alcohol consumption and should be investigated in drinkers meeting criteria for alcohol use disorders.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Effect of Lowering the Dose of Varenicline on Alcohol Self-administration in Drinkers With Alcohol Use Disorders

Verplaetse

Pittman

Shi

et al. 2016

Journal of Addiction Medicine

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“…This hypothesis was first put forth by Reid and colleagues (2007) who conducted a laboratory study of topiramate's effects during a period of brief smoking abstinence and found that the medication had no effect on cue-induced craving and actually enhanced withdrawal. In contrast, each of the first-line smoking cessation aids has been found to have anticraving effects (Kotlyar et al, 2011; Ravva et al, 2015; Shiffman, 2008) with bupropion and varenicline also mitigating withdrawal-related negative affect (Cinciripini et al, 2013; Foulds et al, 2013). …”

Section: Discussionmentioning

confidence: 98%

A Randomized Trial Evaluating Whether Topiramate Aids Smoking Cessation and Prevents Alcohol Relapse in Recovering Alcohol‐Dependent Men

Anthenelli

Heffner

Wong

et al. 2016

Alcoholism Clin & Exp Res

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Background Alcohol and nicotine dependence frequently co-occur, and quitting smoking might enhance long-term alcohol abstinence. Topiramate appears to help non-alcohol-dependent individuals quit smoking, and our pilot work suggested efficacy only in men. It also prevents relapse to alcohol in recently detoxified alcoholics. We evaluated topiramate in abstinent alcohol-dependent men to assess whether this medication (i) promotes smoking cessation and (ii) prevents alcohol and other drug relapse in the context of smoking cessation treatment. Methods One hundred and twenty-nine alcohol-abstinent (mean ∼6 months) alcohol-dependent male smokers (80% with other substance use disorders) participated in this 12-week randomized, double blind, parallel group comparison of topiramate (up to 200 mg/d) and placebo with a 24-week non-treatment follow-up period. The study was carried out sequentially at 2 academic centers in the Midwest and Southern California between March 23, 2009 and November 20, 2014. All participants received manual-guided smoking cessation counseling combined with medication-focused compliance enhancement therapy. Randomization was block designed by the research pharmacist in a 1:1 ratio. Participants, investigators, and research personnel were masked to treatment assignment. The primary smoking end point was biochemically confirmed 4-week continuous abstinence from smoking during weeks 9 to 12, while the secondary end point was relapse to any drinking or drug use during the entire 36-week evaluation period. Logistic regression was used to determine the effects of topiramate on quitting smoking and alcohol relapse, controlling for relevant covariates. The trial is registered at ClinicalTrials.gov (number NCT00802412) and is now closed. Results Only a small proportion (7.9%) of topiramate-treated participants were able to quit smoking, and this cessation rate was similar to placebo (10.6%; odds ratio = 1.60; 95% confidence interval 0.4, 6.5; p = 0.51). Roughly 30% of the sample had a documented relapse to drinking or drug use during the study, and these rates were similar in the topiramate (20/63; 31.8%) and placebo groups (18/66; 27.3%; p = 0.58). Results of a longitudinal logistic regression model examining time to any alcohol relapse revealed no medication effect. Conclusions Topiramate at a daily dosage of up to 200 mg per day, combined with smoking cessation and medication adherence counseling, had no effects on smoking cessation or the prevention of alcohol or drug relapse in male smokers who were in early or sustained full remission from alcohol and motivated to make a quit attempt. Alternative approaches for treating this high-risk, dually dependent population are needed.

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“…Various clinical trials have demonstrated the effi cacy and safety of VCL in adults who initiate a smoking cessation program. A PK-PD analysis described a model for VCL that included using a two-compartment PK model with a linear PD model with fi rstorder onset/offset rate constants [ 17 ]. Craving reduction scores were associated with VCL plasma concentrations with a rapid onset under 1 h peaking at 3 h and were maintained for the next 4 h (the maximum time period studied).…”

Section: Varenicline (Vcl)mentioning

confidence: 99%

Anti-addiction Agents

Jann

2016

Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents

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Pharmacotherapeutic interventions for addiction focus on treatment and prevention of dependence. Addiction is a complex biological process and its complete underlying pathophysiology remains elusive. Successful treatment involves both short-term and long-term maintenance pharmacologic approaches linked with various psychosocial support avenues. However, specifi c agents have been developed for alcohol, nicotine, and opiate dependence. Disulfi ram has been used since the 1950s as an aversive therapeutic technique where its metabolites when exposed to alcohol lead to the patient experiencing symptoms of nausea and vomiting, encouraging the patient to abstain from alcohol. Acamprosate is indicated for alcohol abstinence maintenance with the chemical component acetyl-homotaurine measured in pharmacokinetic studies. Acamprosate is primarily renally excreted. Varenicline is a partial agonist of the central nicotinic acetylcholine receptor and approved for the treatment of nicotine dependence. Varenicline is mainly renally excreted where a combined pharmacokinetic-pharmacodynamic model described this compound with an open two-compartment pharmacokinetic model with a linear pharmacodynamic model. Naloxone and naltrexone are opiate antagonists used in a variety of clinical settings. Naloxone is a "rescue" agent for opiate overdose. Naltrexone is used for alcohol dependence and available in an oral and a monthly long-acting depot injection. Naloxone has been combined with pentazocine, buprenorphine, and oxycodone to prevent abuse. Levo-alpha acetyl methadol (LAAM) is a potent derivative of methadone but QTc prolongation occurrences have limited its clinical use.

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Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Varenicline on Nicotine Craving in Adult Smokers

Cited by 14 publications

References 35 publications

Effect of Lowering the Dose of Varenicline on Alcohol Self-administration in Drinkers With Alcohol Use Disorders

Effect of Lowering the Dose of Varenicline on Alcohol Self-administration in Drinkers With Alcohol Use Disorders

A Randomized Trial Evaluating Whether Topiramate Aids Smoking Cessation and Prevents Alcohol Relapse in Recovering Alcohol‐Dependent Men

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