Varenicline

Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine receptors, where it acts as a partial agonist – a compound that has both agonist activity, with lower intrinsic efficacy than nicotine, and antagonist activities in the presence of nicotine.

Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to the α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Nicotine competes for the same human α4β2 nAChR binding site for which varenicline has higher affinity. Therefore, varenicline can effectively block nicotine’s ability to fully activate α4β2 receptors and the mesolimbic dopamine system, the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to the α4β2 receptor subtype (Ki=0.15 nM) than to other common nicotinic receptors (α3β4 Ki=84 nM, α7 Ki=620 nM, α1βγδ Ki=3,400 nM), or to non-nicotinic receptors and transporters (Ki>1µM, except to 5-HT₃ receptors: Ki=350 nM).

Pharmacodynamic effects

The efficacy of varenicline in smoking cessation is a result of varenicline’s partial agonist activity at the α4β2 nicotinic receptor where its binding produces an effect sufficient to alleviate symptoms of craving and withdrawal (agonist activity), while simultaneously resulting in a reduction of the rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors (antagonist activity).

Absorption

Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses to healthy volunteers, steady-state conditions were reached within 4 days. Absorption is virtually complete after oral administration and systemic availability is high. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing.

Distribution

Varenicline distributes into tissues, including the brain. Apparent volume of distribution averaged 415 litres (CV= 50) at steady-state. Plasma protein binding of varenicline is low (≤20) and independent of both age and renal function. In rodents, varenicline is transferred through the placenta and excreted in milk.

Biotransformation

Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine and less than 10% excreted as metabolites. Minor metabolites in urine include varenicline N-carbamoylglucuronide and hydroxyvarenicline. In circulation, varenicline comprises 91% of drug-related material. Minor circulating metabolites include varenicline N-carbamoylglucuronide and N-glucosylvarenicline.

In vitro studies demonstrate that varenicline does not inhibit cytochrome P450 enzymes (IC₅₀>6,400 ng/ml). The P450 enzymes tested for inhibition were: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline was shown to not induce the activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.

Elimination

The elimination half-life of varenicline is approximately 24 hours. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion via the organic cationic transporter, OCT2.

Linearity/Non linearity

Varenicline exhibits linear kinetics when given as single (0.1 to 3 mg) or repeated 1 to 3 mg/day doses.

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 medicinal products, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.

Hepatic impairment

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

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), varenicline was efficiently removed by haemodialysis.

Elderly

The pharmacokinetics of varenicline in elderly patients with normal renal function (aged 65-75 years) is similar to that of younger adult subjects.

Paediatric population

Single and multiple-dose pharmacokinetics of varenicline have been investigated in paediatric patients aged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight >55 kg, as assessed by AUC_(0-24), was comparable to that noted for the same doses in the adult population. When 0.5 mg twice daily was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤55 kg compared to that noted in the adult population. Varenicline is not recommended in paediatric patients because its efficacy in this population was not demonstrated.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, fertility and embryo-foetal development. In male rats dosed for 2 years with varenicline, there was a dose-related increase in the incidence of hibernoma (tumour of the brown fat). In the offspring of pregnant rats treated with varenicline there were decreases in fertility and increases in the auditory startle response. These effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Nonclinical data indicate varenicline has reinforcing properties albeit with lower potency than nicotine. In clinical studies in humans, varenicline showed low abuse potential.