Cytisine concentration-effect relationships in human smokers

Abstract

Cytisine is a plant alkaloid that is a partial agonist for the α4β2-nicotinic acetylcholine receptor and is used as a smoking cessation medication (Tabex®). Double-blind, randomised, placebo-controlled trials show that cytisine is more effective than placebo in achieving long-term, continuous abstinence from smoking. At the start of this PhD there was no published information on the pharmacokinetics and metabolism of cytisine in humans or indeed, whether there is any relationship between cytisine exposure and effect. The main aims of this thesis were therefore: to obtain basic pharmacokinetic data for cytisine in humans, to study the effects of cytisine on physiological and psychological measures in smokers and to explore whether these effects could be related to the plasma concentrations of cytisine in human smokers who were instructed to adhere to the standard dosing regimen of Tabex® In order to study the human metabolism and pharmacokinetics of cytisine, a sensitive analytical method using mass spectrometry (LC-MS) was developed and validated. This method was used to support the subsequent pharmacokinetic studies. In the first study, seven participants took a single dose (3 mg) of Tabex® and blood samples were collected at various times up to 24 hours. Cytisine plasma concentrations were measured. In the second study, another set of participants (n=11) took Tabex® using the standard 25-day dosing regimen recommended by the manufacturer. Blood samples were collected and cigarette craving, withdrawal, mood and smoking satisfaction were measured using self-report methods validated in the literature. Following a single dose administration, cytisine peak plasma concentrations typically occurred at 2 hours. Following this, cytisine concentrations declined in a monophasic manner with a mean half-life of 4.8 hours. No metabolites were detected. In the second study, accumulation of cytisine in plasma was observed on day 1. However, with the recommended dosing regimen, cytisine does not reach steady state concentration in plasma. There was also large between-subject variability in cytisine pharmacokinetics. Cytisine appeared to reduce cigarette cravings, but there did not appear to be a simple relationship between craving and cytisine plasma concentration. In summary, this thesis presents the first reported human cytisine pharmacokinetic data. The information gained from these studies may be used to inform the design of future trials that explore different dosing regimens of cytisine.