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

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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.

Methods

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.

Results

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 (ka) was fixed to 0.98 h−1. 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.

Conclusions

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.

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Acknowledgements

The authors thank Dr. M. Kohler Serra, M. Puhl, and B. Koenig for the enrollment and follow-up of study participants. The authors also thank M. Jonzier-Perey, M. Brocard, A.C. Aubert, A. Kottelat, M. Delessert, N. Cochard, and S. Jaquet for the sample analyses; C. Brogli and V. Hodel for the logistic support; E. Retamales for the help with bibliography; and N. Simon for his input on modeling and stimulating discussions.

Funding

This work was supported by a grant from the Tobacco Prevention Fund, Swiss Federal Office of Public Health (06.004879 to C. B. Eap).

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Authors and Affiliations

  1. Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Hospital of Cery, University of Lausanne, Prilly, Switzerland

    Anaïs Glatard, Maria Dobrinas & Chin B. Eap

  2. Service of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland

    Anaïs Glatard, Monia Guidi & Chantal Csajka

  3. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland

    Monia Guidi, Chantal Csajka & Chin B. Eap

  4. Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland

    Jacques Cornuz

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  1. Anaïs Glatard
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  2. Monia Guidi
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  3. Maria Dobrinas
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  4. Jacques Cornuz
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Contributions

Anaïs Glatard wrote the manuscript and analyzed data. Monia Guidi wrote the manuscript and analyzed data. Maria Dobrinas wrote the manuscript, designed the research, and performed the research. Jacques Cornuz wrote the manuscript and designed research. Chantal Csajka wrote the manuscript and analyzed data. Chin B. Eap wrote the manuscript, designed research, and obtained the funds.

Corresponding authors

Correspondence to Chantal Csajka or Chin B. Eap.

Ethics declarations

The study was approved by the Ethics Committee of the Lausanne University Medical School and by the Swiss Agency for Therapeutic Products (Swissmedic, Bern, Switzerland). Written informed consent was obtained from all participants.

Conflict of interest

CBE received honoraria for conferences or teaching CME courses from Forum für Medizinische Fortbildung, Janssen-Cilag, Lundbeck, Mepha, Otsuka, Sandoz, Servier, Vifor-Pharma, and Zeller during the past 3 years and for writing a review article for the journal Dialogues in clinical neurosciences (Servier). He received an unrestricted educational research grant from Takeda during the past 3 years. All the other authors declare that they have no conflict of interest.

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Glatard, A., Guidi, M., Dobrinas, M. et al. Influence of body weight and UGT2B7 polymorphism on varenicline exposure in a cohort of smokers from the general population. Eur J Clin Pharmacol 75, 939–949 (2019). https://doi.org/10.1007/s00228-019-02662-9

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