Hélène M. Faessel

Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α₄β₂ nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of varenicline. In vitro, varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in varenicline clinical trials, with an incidence that was sexrelated and increased with varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of varenicline simplify its use in clinical practice.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? • Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in young adult and elderly smokers and subjects with impaired renal function.• Varenicline pharmacokinetics is linear over the recommended dose range.• Varenicline total clearance is linearly related to its renal clearance.• Both are progressively reduced as renal function declines, which results in a progressive increase in varenicline systemic exposure and prolonged half‐life. WHAT THIS STUDY ADDS? • This work provides an integrated model‐based analysis of varenicline pharmacokinetics across multiple studies in the target patient population.• The model describes the impact of patient‐specific covariates, such as renal function, and provides a rationale for dose adjustment.• The resulting model also provides a means to predict individual‐specific drug exposures to clinical responses in subsequent analyses.AIMS: To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers.METHODS: Data were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration–time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling.RESULTS: A two‐compartment model with first‐order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h⁻¹ (10.2, 10.6); V₂/F, 337 l (309, 364); V₃/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h⁻¹ (1.39, 3.79); K_a, 1.69 h⁻¹ (1.27, 2.00); and A_lag, 0.43 h (0.37, 0.46). Random interindividual variances were estimated for K_a[70% coefficient of variation (CV)], CL/F (25% CV), and V₂/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h⁻¹ for a typical subject with normal renal function (CLcr = 100 ml min⁻¹) to 4.4 l h⁻¹ for a typical subject with severe renal impairment (CLcr = 20 ml min⁻¹), which corresponds to a 2.4‐fold increase in daily steady‐state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics.CONCLUSIONS: Renal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day⁻¹, which is half the recommended dose, is indicated for subjects with severe renal impairment.

This study investigated the effect of varenicline on the multiple-dose pharmacokinetics of digoxin. Eighteen smokers were randomized to receive digoxin (Lanoxicaps® 0.2 mg QD) with varenicline 1 mg BID or placebo for 14 days. Varenicline had no clinically relevant effect on the digoxin steady-state exposure, as evidenced by the 90% confidence intervals for the ratios of AUC_0–24 (87.5–108%) and C_min (83.8–116%) wholly contained within 80–125%. Digoxin C_max and T_max remained unchanged in the presence of varenicline, consistent with no apparent alteration in digoxin bioavailability. A minimal 11.3% increase in digoxin renal clearance was noted during varenicline treatment while having no impact on its systemic exposure. Results are supported by mechanistic evidence in Caco-2 cell monolayers that varenicline is neither a P-gp substrate nor an inhibitor of P-gp-mediated efflux of digoxin. Co-administration of varenicline and digoxin was well tolerated. The results suggest that digoxin can be safely administered with varenicline without the need for dose adjustment.

Varenicline is predominantly eliminated unchanged in urine, and active tubular secretion partially contributes to its renal elimination. Transporter inhibition assays using human embryonic kidney 293 cells transfected with human renal transporters demonstrated that high concentrations of varenicline inhibited substrate uptake by hOCT2 (IC(50)=890 microM), with very weak or no measurable interactions with the other transporters hOAT1, hOAT3, hOCTN1, and hOCTN2. Varenicline was characterized as a moderate-affinity substrate for hOCT2 (K(m)=370 microM) and its hOCT2-mediated uptake was partially inhibited by cimetidine. Co-administration of cimetidine (1,200 mg/day) reduced the renal clearance of varenicline in 12 smokers, resulting in a 29.0% (90% CI: 21.5%-36.9%) increase in systemic exposure. This increase is not considered clinically relevant, as it should not give rise to safety concerns. Consequently, it can be reasonably expected that other inhibitors of hOCT2 would not cause greater renal interactions with varenicline than that seen with the efficient hOCT2 inhibitor cimetidine.

Varenicline is a novel and selective α4β2 nicotinic acetylcholine receptor partial agonist developed for smoking cessation. The primary objectives of this double‐blind, placebo‐controlled, dose‐escalation study were to determine the pharmacokinetics, safety, and tolerability of multiple oral doses of varenicline given as tablets once (1 mg, 2 mg, and 3 mg) or twice (1 mg) daily to healthy adult smokers. Within each dose level, 8 subjects were randomized to varenicline and 4 subjects to placebo. Varenicline was well tolerated at doses up to and including 2 mg daily. Dose‐proportional increases in maximum observed plasma concentrations and area under the plasma concentration‐time curve from time zero to the end of the dosing interval values were observed between the 1‐mg and 2‐mg daily doses of varenicline. Once‐ and twice‐daily dosing resulted, on average, in an approximate 2‐ and 3‐fold increase in varenicline systemic exposure, respectively, compared with single dose. There was no evidence of concentration‐ or time‐dependent changes in the pharmacokinetics of varenicline upon repeat dosing.