STEADY-STATE PHARMACOKINETICS AND DOSE RELATIONSHIP OF NICOTINE DELIVERED FROM NICODERM(R) (NICOTINE TRANSDERMAL SYSTEM)

An open-label, randomized, crossover study determined nicotine pharmacokinetics at steady state of a new Nicotine Transdermal System in 24 healthy adult male smokers. Three doses were each administered for 5 days: 7, 14 and 21 mg nicotine per day. Plasma nicotine concentrations reached steady state by the third day and were sustained throughout the 24-hour application periods. Mean steady-state nicotine and cotinine area under the curve (AUC0-24), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), average plasma concentration (Cavg), and total urinary cotinine were proportional to the dose of nicotine released in vitro from Nicotine Transdermal System. Time to reach peak concentration (tmax), half-life (t1/2), relative degree of fluctuation (DF) in steady-state plasma nicotine and cotinine concentrations, and renal cotinine clearance were similar for all three dosages, indicating linear pharmacokinetics and no change in nicotine metabolism with increasing dose. Findings from a second study also reflect the linear dose relationship for this Nicotine Transdermal System within the 7 to 21 mg/day dosage range. Bioequivalence based on the confidence interval test was demonstrated for a single application of Nicotine Transdermal System 21 mg/day and the same total dosage achieved by combined administration of Nicotine Transdermal System 7 mg/day plus Nicotine Transdermal System 14 mg/day, although there were small statistical differences. This Nicotine Transdermal System has a well-defined pharmacokinetic profile, with sustained plasma nicotine concentrations, and nicotine pharmacokinetics that are independent of the dose of this Nicotine Transdermal System.