Mechanism Of Action

Varenicline binds with high affinity and selectivity at α₄β₂ neuronal nicotinic acetylcholine receptors. The efficacy of CHANTIX in smoking cessation is believed to be the result of varenicline's ype of the nicotinic receptor where its binding produces agonistactivity at sub-t activity, while simultaneously preventing nicotine binding to α₄β₂ receptors.

Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to α₄β₂ 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 α₄β₂ 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 α₄β₂ receptors than to other common nicotinic receptors ( > 500-fold α₃β₄, > 3500-fold α₇, > 20,000-fold α₁βγδ ), 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 CHANTIX in subjects with renal impairment (See DOSAGE AND ADMINISTRATION). Additionally, in subjects with ESRD, varenicline was efficiently removed by hemodialysis (See OVERDOSAGE).

Geriatric

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