Multiple-dose pharmacokinetics of the selective nicotinic receptor partial agonist, varenicline, in healthy smokers.
Varenicline is a novel and selective alpha4beta2 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.
Faessel
Hélène M
HM
Department of Clinical Pharmacokinetics and Pharmacodynamics, Pfizer Global Research and Development, Eastern Point Road/MS 8260-2309, Groton, CT 06340, USA. Helene.M.Faessel@pfizer.com
Gibbs
Megan A
MA
Clark
David J
DJ
Rohrbacher
Kevin
K
Stolar
Marilyn
M
Burstein
Aaron H
AH
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001552:Benzazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003367:Cotinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007024:Hypotension, Orthostatic / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009538:Nicotine / Q000097:blood; D010352:Patient Dropouts; D011810:Quinoxalines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism; D016540:Smoking Cessation / Q000379:methods; D000074606:Smoking Prevention; D013607:Tablets; D000068580:Varenicline; D014839:Vomiting / Q000139:chemically induced
D001552:Benzazepines; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D013607:Tablets; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D003367:Cotinine; D000068580:Varenicline