Pharmacokinetic investigation of a nicotine sublingual tablet

Objective: To evaluate the pharmacokinetics of a new 2-mg nicotine sublingu al tablet under varying conditions of use. Methods: The pharmacokinetics of the 2-mg nicotine sublingual tablet were i nvestigated in four separate studies involving healthy adult volunteer smok ers: (1) a multiple-dose comparison with 2-mg nicotine chewing gum (n=24; 1 3 males, 11 females), (2) a dose-proportionality study comparing single dos es of 2, 4 and 6 mg (n=21, 10 males, 11 females), (3) an evaluation of the effect of incorrect tablet use, i.e. chewing the tablet followed by either immediate or delayed swallowing (n = 19, 10 males, 9 females), and (4) the effect of oral and gastric pH on nicotine absorption from the tablet (n=20; 11 males, 9 females). Study parameters were maximal plasma concentration ( C-max), time to C-max (t(max)), and area under the plasma concentration-tim e curve (AUC). Results: The plasma nicotine profiles were similar following repeated admin istration of the sublingual tablet and the 2-mg nicotine chewing gum (mean C-max 13.2 versus 14.4 ng/ml, median t(max) 20 versus 20 min, mean AUC(11-1 2) 12.4 versus 13.5 ng/ml per hour) with no statistically significant diffe rence between the two treatments. The pharmacokinetics of the 4- and 6-mg d oses were non-linear compared to the 2-mg dose, probably as a result of mor e of the dose being swallowed and undergoing first-pass metabolism in the l iver. The mean C-max for the 2-, 4- and 6-mg dose was 3.8 +/- 1.0, 6.8 +/- 2.1, and 9.0 +/- 3.3 ng/ml, respectively, and in terms of dose proportional ity the relative bioavailability of the 4- and 6-mg dose was 0.82 and 0.71, respectively. Incorrect tablet use, i.e. chewing the tablet and immediate swallowing decreased nicotine bioavailability both in terms of rate and ext ent. Mean C-max was 12.1 ng/ml (correct use), 10.3 ng/ml (chewing and immed iate swallowing), and 12.1 ng/ml (chewing and delayed swallowing). Correspo nding mean values for AUC(9-10) were 11.6, 9.6 and 11.2 ng/ml per hour. The re were no significant differences between 'alkaline mouth' versus control, 'acidic mouth' versus control or 'alkaline stomach' versus control, but the rate of nicotine absorption was increased at alkaline compared to acidic o ral pH (mean C-max 6.1 versus 4.9 ng/ml, P = 0.003; median t(max) 60 versus 90 min, P = 0.0002). Conclusion: The pharmacokinetic profile of the nicotine 2-mg tablet was sim ilar to that of the 2-mg nicotine chewing gum. Absorption of nicotine from the tablet was nonlinear at higher doses (two or three tablets). Chewing th e tablet and keeping the remains in the mouth or concurrent use of acidic b everages or antacids are equivalent to recommended sublingual use during no rmal oral pH conditions.