Population pharmacokinetic analysis of varenicline in adult smokers

To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers.

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.

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); V(2)/F, 337 l (309, 364); V(3)/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 V(2)/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.

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.