Varenicline exposure is associated with abstinence from smoking in a cohort of smokers from the general population
Anais Glatard (1,2), Monia Guidi (2,3), Maria Dobrinas (1), Jacques Cornuz (4), Chin B. Eap (1,3) and Chantal Csajka (2,3)*
(1) Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Hospital of Cery, Prilly, Switzerland (2) Division of Clinical Pharmacology, Service of Biomedicine, Department of Laboratory, Lausanne University Hospital, Lausanne, Switzerland (3) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland (4) Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland *joint corresponding authors
Objectives: The overall abstinence rate after varenicline treatment at the effective dose is reported to be less than 35%. High interindividual variability in plasma concentrations of varenicline may lead to suboptimal drug concentration. This study aimed to characterize the genetic and non-genetic sources of variability of varenicline pharmacokinetics and to relate them to drug effectiveness.
Methods: 82 smokers (121 varenicline concentrations) were genotyped for common polymorphisms in Uridine glucuronosyltransferase (UGT) 2B7, Organic Cation Transporter (OCT) 2 and some nuclear factors genes. Varenicline pharmacokinetics was analyzed using non-linear mixed effect modeling in NONMEM. For each concentration, the area under the concentration-time curve over 24 hours, AUC0-24, was computed in NONMEM analytically based on the dose history and the pharmacokinetic parameters. Correlations between AUC0-24 and withdrawal symptoms or carbon monoxide and cotinine levels were assessed by the Pearson correlation coefficient and linear mixed modeling, respectively.
Results: A one-compartment model with first order absorption and elimination appropriately described the 121 varenicline concentrations. Varenicline systemic clearance was 8.51 L/h (CV 25.7%), the volume of distribution was 228 L and the absorption rate was fixed to 0.98 h-1. Varenicline clearance increased by 68% with body weight doubling and was found to be 21% higher in UGT2B7 rs7439366 CC genotype carriers compared with CT and TT carriers. These covariates explained 14% and 9% of the interindividual variability in varenicline clearance, respectively. No correlation between the AUC0-24 and scores of appetite/weight gain (p=0.5) or nicotine craving (p=0.2) was found. With an AUC0-24 increase of 1 ng-1.h-1.mL, carbon monoxide and cotinine levels were significantly decreased by 0.06 ppm (95%CI= -0.07 ; -0.04) and by 0.63 ng/mL (95%CI= -0.92 ; -0.38), respectively.
Conclusions: Body weight and genetic polymorphisms of UGT2B7 play a significant role in varenicline exposure variability. Significant association was identified between varenicline AUC0-24 and two biomarkers of abstinence from smoking, therefore dosage titration based on carbon monoxide or cotinine might increase the treatment success. Although the limited amount of pharmacokinetic data would require further analysis, the originality of this work relies in the analysis of the influence of genetic factors on varenicline clearance.
