Mechanism Of Action
* Varenicline binds with high affinity and selectivity at (alpha)4(beta)2 neuronal nicotinic acetylcholine receptors.
The efficacy of SmokeLESS in smoking cessation is believed to be the result of varenicline's activity at a sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to (alpha)4(beta)2 receptors.

* Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to (alpha)4(beta)2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine.
Varenicline blocks the ability of nicotine to activate (alpha)4(beta)2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking.
Varenicline is highly selective and binds more potently to (alpha)4(beta)2 receptors than to other common nicotinic receptors (>500-fold (alpha)3(beta)4, >3500-fold (alpha)7, >20,000-fold (alpha)1(beta)(gamma)[dgr ]), or to non-nicotinic receptors and transporters (>2000-fold).
Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.

Pharmacokinetics

Absorption/Distribution

Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration.
Following administration of multiple oral doses of varenicline, steady-state conditions were reached within 4 days.
Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after single or repeated doses.
In a mass balance study, absorption of varenicline was virtually complete after oral administration and systemic availability was high.
Oral bioavailability of varenicline is unaffected by food or time-of-day dosing.
Plasma protein binding of varenicline is low (</=20%) and independent of both age and renal function.

Metabolism/Elimination

The elimination half-life of varenicline is approximately 24 hours.
Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine.
Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2.

Pharmacokinetics In Special Patient Populations
There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.

Renal impairment
Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance >50 mL/min and </=80 mL/min).
In patients with moderate renal impairment (estimated creatinine clearance >/= 30 mL/min and </=50 mL/min), varenicline exposure increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance >80 mL/min).
In subjects with severe renal impairment (estimated creatinine clearance <30 mL/min), varenicline exposure was increased 2.1-fold.
In subjects with end-stage-renal disease (ESRD) undergoing a three hour session of hemodialysis for three days a week, varenicline exposure was increased 2.7-fold following 0.5 mg once daily administration for 12 days.
The plasma Cmax and AUC of varenicline noted in this setting were similar to healthy subjects receiving about 1 mg twice daily.
Caution is warranted with the use of SmokeLESS in subjects with renal impairment.
Additionally, in subjects with ESRD, varenicline was efficiently removed by hemodialysis.

Geriatric
A combined single and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given QD or BID to 16 healthy elderly male and female smokers (aged 65-75 yrs) for 7 consecutive days was similar to that of younger subjects.

Pediatric
* Because the safety and effectiveness of SmokeLESS in pediatric patients have not been established, SmokeLESS is not recommended for use in patients under 18 years of age.

* When 22 pediatric patients aged 12 to 17 years (inclusive) received a single 0.5 mg and 1 mg-dose of varenicline, the pharmacokinetics of varenicline was approximately dose proportional between the 0.5 mg and 1 mg doses.
Systemic exposure, as assessed by AUC(0-∞), and renal clearance of varenicline were comparable to those of an adult population.

Hepatic impairment
Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic insufficiency.

Drug-Drug Interactions

* Drug interaction studies were performed with varenicline and digoxin, warfarin, transdermal nicotine, bupropion, cimetidine and metformin.
No clinically meaningful pharmacokinetic drug-drug interactions have been identified.

* In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymes (IC50 >6400 ng/mL): 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5.
Also, in human hepatocytes in vitro, varenicline does not induce the cytochrome P450 enzymes 1A2 and 3A4.

* In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations.
Therefore, drugs that are cleared by renal secretion (e.g. metformin) are unlikely to be affected by varenicline.

* In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter, OCT2.

Co-administration with inhibitors of OCT2 may not require a dose adjustment of SmokeLES as the increase in systemic exposure to SmokeLESS is not expected to be clinically meaningful.

Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of SmokeLESS and therefore a dose adjustment of SmokeLESS would not be required.

Metformin: When co-administered to 30 smokers varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of metformin (500 mg BID), which is a substrate of OCT2.
Metformin had no effect on varenicline steady-state pharmacokinetics.

Cimetidine: Co-administration of an OCT2 inhibitor, cimetidine (300 mg QID), with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21.5%, 36.9%) due to a reduction in varenicline renal clearance.

Digoxin: Varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose in 18 smokers.

Warfarin: Varenicline (1 mg BID) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin in 24 smokers.
Prothrombin time (INR) was not affected by varenicline.
Smoking cessation itself may result in changes to warfarin pharmacokinetics.

Use with other therapies for smoking cessation:
Bupropion: Varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of bupropion (150 mg BID) in 46 smokers.
The safety of the combination of bupropion and varenicline has not been established.

Nicotine replacement therapy (NRT): Although co-administration of varenicline (1 mg BID) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of nausea, headache, vomiting, dizziness, dyspepsia and fatigue was greater for the combination than for NRT alone.
In this study, eight of twenty-two (36%) subjects treated with the combination of varenicline and NRT prematurely discontinued treatment due to adverse events, compared to 1 of 17 (6%) of subjects treated with NRT and placebo.

Safety and efficacy of SmokeLESS in combination with other smoking cessation therapies have not been studied.