Pharmacodynamic and pharmacokinetic profiles of the α4β2 nicotinic acetylcholine receptor partial agonist varenicline, a smoking cessation aid

Abstract

This review describes the role of ?4?2 containing nicotinic acetylcholine receptors in the mesolimbic reward pathway in the neurobiology of nicotine addiction and discusses the rationale for targeting this receptor with partial agonists as novel smoking cessation agents. Varenicline is a ?4?2 nicotinic acetylcholine receptor partial agonist that is a smoking cessation aid with a dual mechanism of action: relief of craving and withdrawal symptoms, as well as attenuation of nicotine reinforcement. The pharmacological profile of varenicline is consistent with that of a potent and selective partial agonist at the target receptor, both in in vitro and in vivo neurochemical and behavioral models. Varenicline was nominated for full clinical development in 1997, and later approved in the US and Europe as a smoking cessation aid in 2006. The recommended dose of varenicline is 1 mg BID for 12 weeks after an initial titration week in adult smokers motivated to stop smoking. The pharmacokinetics of varenicline is linear and consistent regardless of smoking status, age, gender or ethnic background. Varenicline is largely eliminated unchanged in the urine, and consequently a dose adjustment is warranted for patients with severe renal insufficiency. Although varenicline is currently not approved for use in smokers under age 18, its pharmacokinetic and tolerability profile in adolescents appeared generally similar to adults. Several large clinical trials have consistently shown the efficacy, tolerability and safety of varenicline in various ethnic smoking populations and in adult smokers with co-morbid chronic pulmonary or cardiovascular disease. Additional clinical studies in special patient populations are currently ongoing.