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.
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); 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); Ka, 1.69 h−1 (1.27, 2.00); and Alag, 0.43 h (0.37, 0.46). Random interindividual variances were estimated for Ka[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.
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.