Population pharmacokinetics of nicotine in Thai smokers

Abstract

Despite the popularity of nicotine gum in Thailand, population pharmacokinetics of nicotine gum in Thai population has not been investigated yet. This study aimed to develop a population pharmacokinetic model to quantify the effects of genetic and nongenetic factors to nicotine pharmacokinetics after administration of nicotine gum to adult Thai smokers. A population pharmacokinetic analysis was performed using secondary data collected from a previous clinical trial assessing cytochrome P450 2A6 (CYP2A6) genotypes in Thai smokers. Eighteen healthy adult smokers were included in the study. Blood samples were collected at pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4.5, and 6h after receiving a single dose of 2 mg nicotine gum. Population pharmacokinetics of nicotine was performed using nonlinear mixed effect modeling. One-compartment with 1st order elimination and 1st order absorption with 6-transit compartments best described the data. Enzymatic activity of different CYP2A6 genotypes was a significant covariate on clearance of nicotine. Apparent elimination clearance (CL/F) and apparent volume of distribution (V/F) of nicotine for a typical smoker with normal-function CYP2A6 genotype (or 100% CYP2A6 activity) was 266 L/h and 851 L respectively. Results of 1,000 bootstrapping and visual predictive check showed that model was valid and appropriate. This first report on population pharmacokinetics of nicotine gum in Thai smokers provided the pharmacokinetic model of nicotine and quantified CL/F of nicotine for smokers with different CYP2A6 genotypes.