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

Varenicline is a novel selective α4β2 nicotinic acetylcholine partial agonist developed for smoking cessation. Single-and multiple dose studies were conducted to investigate pharmacokinetics, safety, and tolerability of varenicline in healthy male Japanese smokers. The single-dose study was conducted as a double-blind, placebo-controlled, 4-way crossover study. Subjects received varenicline (0.25, 0.5, 1.0, 2.0 mg) or placebo at an interval of 2 weeks. The double-blind, placebo-controlled multiple-dose study was conducted as 2 cohorts, each consisting of 8 subjects randomized to varenicline tablets twice daily (0.5 or 1.0 mg) and 4 subjects randomized to placebo administered for 14 days. In both studies, varenicline was well tolerated at doses up to and including 2 mg daily. Dose-proportional increases in varenicline systemic exposure were observed following single and multiple dosing. Peak plasma concentrations generally occurred within 2 to 4 hours after dosing. Mean half-life estimates ranged from approximately 13 to 19 hours after single dosing and 24 to 28 hours after repeat dosing. Consistent with this, both 0.5 and 1.0 mg twice daily resulted, on average, in an approximate 3-fold increase in varenicline systemic exposure. These results showed that the single- and multiple-dose pharmacokinetics of varenicline in Japanese smokers were similar to those previously reported in Western smokers.