serval:BIB_1B9CBBB244BC
Influence of body weight and UGT2B7 polymorphism on varenicline exposure in a cohort of smokers from the general population.
10.1007/s00228-019-02662-9
000472049600008
30868192
Glatard
A.
author
Guidi
M.
author
Dobrinas
M.
author
Cornuz
J.
author
Csajka
C.
author
Eap
C.B.
author
article
2019-07
European journal of clinical pharmacology
1432-1041
0031-6970
journal
75
7
939-949
The abstinence rate to tobacco after varenicline treatment is moderate and might be partially affected by variability in varenicline concentrations. This study aimed at characterizing the sources of variability in varenicline pharmacokinetics and to relate varenicline exposure to abstinence.
The population pharmacokinetic analysis (NONMEM®) included 121 varenicline concentrations from 82 individuals and tested the influence of genetic and non-genetic characteristics on apparent clearance (CL/F) and volume of distribution (V/F). Model-based average concentrations over 24 h (Cav) were used to test the impact of varenicline exposure on the input rate (Kin) expressed as a function of the number of cigarettes per day in a turnover model of 373 expired carbon monoxide levels.
A one-compartment model with first-order absorption and elimination appropriately described varenicline concentrations. CL/F was 8.5 L/h (coefficient of variation, 26%), V/F was 228 L, and the absorption rate (k <sub>a</sub> ) was fixed to 0.98 h <sup>-1</sup> . CL/F increased by 46% in 100-kg individuals compared to 60-kg individuals and was found to be 21% higher in UGT2B7 rs7439366 TT individuals. These covariates explained 14% and 9% of the interindividual variability in CL/F, respectively. No influence of varenicline Cav was found on Kin in addition to the number of cigarettes.
Body weight mostly and to a smaller extent genetic polymorphisms of UGT2B7 can influence varenicline exposure. Dose adjustment based on body weight and, if available, on UGT2B7 genotype might be useful to improve clinical efficacy and tolerability of varenicline.
Adult
Body Weight
Carbon Monoxide/metabolism
Dose-Response Relationship, Drug
Female
Genotype
Glucuronosyltransferase/genetics
Humans
Male
Middle Aged
Models, Biological
Polymorphism, Single Nucleotide
Smokers
Smoking Cessation
Smoking Cessation Agents/blood
Smoking Cessation Agents/pharmacokinetics
Smoking Cessation Agents/pharmacology
Varenicline/blood
Varenicline/pharmacokinetics
Varenicline/pharmacology
Young Adult
Dose individualization
Pharmacogenetics
Pharmacokinetics
Varenicline
Variability
eng
60_published
peer-reviewed
Publication types: Clinical Trial ; Journal Article
Publication Status: ppublish
University of Lausanne
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