Single-dose pharmacokinetics of varenicline, a selective nicotinic receptor partial agonist, in healthy smokers and nonsmokers.
Varenicline is a novel and selective alpha4beta2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double-blind, placebo-controlled, single-dose, dose-escalation study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. Subjects received one single oral administration of varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time-of-day dosing did not affect the pharmacokinetics of varenicline.
Faessel
Hélène M
HM
Department of Clinical Pharmacokinetics and Pharmacodynamics, Pfizer Global Research and Development, Groton, Connecticut, USA.
Smith
Bill J
BJ
Gibbs
Megan A
MA
Gobey
Jason S
JS
Clark
David J
DJ
Burstein
Aaron H
AH
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001552:Benzazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006262:Health; D006801:Humans; D008297:Male; D008875:Middle Aged; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011810:Quinoxalines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012907:Smoking; D000068580:Varenicline
D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D000068580:Varenicline