Multiple-Dose Pharmacokinetics of the Selective Nicotinic Receptor Partial Agonist, Varenicline, in Healthy Smokers

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.