Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Hospital of Cery, University of Lausanne, Prilly, Switzerland.
Service of Clinical Pharmacology, Department of Laboratories, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
Eur J Clin Pharmacol. 2019 Jul;75(7):939-949. doi: 10.1007/s00228-019-02662-9. Epub 2019 Mar 13.
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) was fixed to 0.98 h. 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.
维拉唑尼治疗后的戒烟率适中，其可能部分受到维拉唑尼浓度变异性的影响。本研究旨在描述维拉唑尼药代动力学变异性的来源，并将维拉唑尼暴露与戒烟相关联。
群体药代动力学分析（NONMEM®）纳入了 82 名个体的 121 个维拉唑尼浓度数据，检测了遗传和非遗传特征对表观清除率（CL/F）和分布容积（V/F）的影响。基于模型的 24 小时平均浓度（Cav）用于测试维拉唑尼暴露对输入率（Kin）的影响，Kin 作为每日吸烟量的函数，在一个 373 个呼出一氧化碳水平的周转率模型中表达。
一个具有一级吸收和消除的单室模型适当描述了维拉唑尼的浓度。CL/F 为 8.5 L/h（变异系数为 26%），V/F 为 228 L，吸收速率（k）固定为 0.98 h。与 60-kg 个体相比，100-kg 个体的 CL/F 增加了 46%，并且在 UGT2B7 rs7439366 TT 个体中发现 CL/F 增加了 21%。这些协变量分别解释了 CL/F 个体间变异性的 14%和 9%。除了吸烟量外，维拉唑尼 Cav 对 Kin 没有影响。
体重主要且较小程度上 UGT2B7 的遗传多态性可以影响维拉唑尼的暴露。基于体重和如果可用的话基于 UGT2B7 基因型的剂量调整可能有助于提高维拉唑尼的临床疗效和耐受性。
