Anaïs Glatard (1,2), Monia Guidi (2,3), Maria Dobrinas (1), Jacques Cornuz (4), Chantal Csajka (2,3)* and Chin B. Eap (1,3)*
(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: Varenicline is a partial agonist of the α4β2 nicotinic acetylcholine receptor, and is widely used for smoking cessation. 90% of the dose administered is eliminated unchanged in urine, notably via OCT2 and the most abundant metabolite is obtained by glucuronidation via UGT2B71. Varenicline has been proven to be generally effective at 1 mg twice daily1,2, however inter-individual variability in the quitting rate is observed3,4, that might be linked to the high reported variability in blood concentrations. The aim of this work was to assess whether genetics factors can explain a part of the variability in varenicline blood levels and therefore its effectiveness.
Methods: Varenicline blood levels were collected in 82 patients during a smoking cessation program with information on abstinence and scores of cigarette withdrawal symptoms. Nineteen single nucleotide polymorphisms of the OCT2, UGT2B7 and nuclear receptors that regulate OCT transporters were selected for analysis and genotyped using the Cardio-MetaboChip (Illumina). The structural PK model development and the covariate analysis were performed by non-linear mixed effect modelling using NONMEM®. Associations between varenicline exposure, defined by the model-based cumulated area under the concentration–time curve (AUCcum), and abstinence as well as withdrawal scores were evaluated in R.
Results: A one-compartment model with first order absorption and elimination appropriately described the 121 varenicline concentrations. Varenicline systemic clearance (CL) 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. An allometric power function with the allometric exponent fixed to 0.75 described adequately the relationship between CL and body weight (BW), leading to a 68% increase in CL upon BW doubling. UGT2B7 rs7439366 C/C carriers were found to have 21% higher CL than T/T and C/T carriers. BW and the UGT2B7 rs7439366 explained 14% and 9% of the inter-individual variability on CL, respectively. AUCcum had a significant positive effect on abstinence rate (OR=12.7; 95%CI=4.3-47.0). No association was found between withdrawal scores and AUCcum.
Conclusions: BW and a genetic polymorphism of UGT2B7 significantly contribute to varenicline plasma concentrations variability. Our results indicate that cumulative exposure to varenicline is associated with abstinence and that dosage titration based on response might increase treatment sucess.
References:
[1] Faessel HM, Obach RS, Rollema H, et al. A Review of the Clinical Pharmacokinetics and pharmacodynamics of Varenicline for Smoking Cessation. Clin Pharmacokinet 2010 ; 49(12) :799-816
[2] Reus VI, Obach RS, Coe JW, et al. Varenicline: new treatment with efficacy in smoking cessation. Drugs Today (Barc). 2007;43(2):65-75.
[3] Cahill K, Stead LF, Lancaster T, et al. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2012;4:CD006103
[4] Fiore MC, Baker TB. Treating Smokers in the Health Care Setting. N Engl J Med. 2011;29;365(13):1222-31
Reference: PAGE 25 (2016) Abstr 5766 [www.page-meeting.org/?abstract=5766]
Poster: Drug/Disease modeling - Other topics