Influence of body weight and UGT2B7 polymorphism on varenicline exposure in a cohort of smokers from the general population.

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Serval ID
serval:BIB_1B9CBBB244BC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Influence of body weight and UGT2B7 polymorphism on varenicline exposure in a cohort of smokers from the general population.
Journal
European journal of clinical pharmacology
Author(s)
Glatard A., Guidi M., Dobrinas M., Cornuz J., Csajka C., Eap C.B.
ISSN
1432-1041 (Electronic)
ISSN-L
0031-6970
Publication state
Published
Issued date
07/2019
Peer-reviewed
Oui
Volume
75
Number
7
Pages
939-949
Language
english
Notes
Publication types: Clinical Trial ; Journal Article
Publication Status: ppublish
Abstract
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.
Keywords
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
Pubmed
Web of science
Create date
28/03/2019 9:37
Last modification date
04/01/2020 7:17
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