A Time-to-Event Model Relating Integrated Craving to Risk of Smoking Relapse Across Different Nicotine Replacement Therapy Formulations.

Smoking increases the risk of cancer and other diseases, causing an estimated 7 million deaths per year. Nicotine replacement therapy (NRT) reduces craving for smoking, therefore, increasing an individual's probability to remain abstinent. In this work, we for the first time quantitatively described the relationship between craving and smoking abstinence, using retrospectively collected data from 19 studies, including 3 NRT formulations (inhaler, mouth spray, and patch) and a combination of inhaler and patch. Smokers motivated to quit were included in the NRT or placebo arms. Integrated craving (i.e., craving over a period of time) was assessed with 4-category, 5-category, or 100-mm visual analogue scale. The bounded integer model was used to assess latent craving from all scales. A time-to-event model linked predicted integrated craving to the hazard of smoking relapse. Available data included 9,323 adult subjects, observed for 3 weeks up to 2 years. At the study end, 9% (11% for NRT and 5% for placebo), on average, remained abstinent according to the protocol definition. A Gompertz-Makeham hazard best described the data, with a hazard of smoking relapse decreasing over time. Latent integrated craving was positively related to the hazard of smoking relapse, through a sigmoidal maximum effect function. For the same craving, being on NRT was found to reduce the hazard of relapse by an additional 30% compared with placebo. This work confirmed that low craving is associated with a high probability of remaining smoking abstinent and that NRT, in addition to reducing craving, increases the probability of remaining smoking abstinent.

Nicotine Population Pharmacokinetics in Healthy Smokers After Intravenous, Oral, Buccal and Transdermal Administration.

BACKGROUND: In 4 decades, numerous nicotine replacement therapy products have been developed. Population pharmacokinetic models can support exposure-response modeling and inform nicotine replacement therapy product development, but only limited model-based cross-study population pharmacokinetic analyses for nicotine replacement therapy products have been published. OBJECTIVES: The aim of this retrospective analysis was to assess the population pharmacokinetics of nicotine across intravenous, oral, transdermal and oromucosal (mouth spray, chewing gum, lozenge and inhaler) routes and formulations in healthy smoking subjects. METHODS: Data on 930 unique subjects (46,016 observations) from 29 single- and repeated-dose studies with multiple formulations across intravenous, oral, transdermal and oromucosal routes of administration were included. Data from intravenous and extravascular routes of administration were modelled separately for run efficiency reasons. For developing extravascular models, clearance and disposition parameters and their inter-individual variabilities were fixed to the estimates for intravenously delivered nicotine. Detectable pre-dose nicotine concentrations were modelled as a hypothetical nicotine bolus into the central compartment at the start of wash-out. Modelling repeated-dose oral and buccal administrations required a time-dependent increase in clearance or decrease in bioavailability to describe the data adequately. RESULTS: Disposition of intravenous nicotine was best described by a three-compartment model with initial and terminal half-lives of 7 min and 4.5 h, respectively, and the absorption of single oral doses was best described with a first-order absorption rate constant of 1.55 h-1. The data of buccal formulations were modelled with parallel oromucosal absorption and gastrointestinal absorption of a part of the dose that is swallowed. For transdermal nicotine, parallel zero- and first-order release from the patch and a transit-compartment absorption model best described the data. Key pharmacokinetic parameters were reliably estimated, with typical values for clearance (67 L/h for a 70-kg subject), volume of distribution (4.3 L/kg), oral bioavailability (40%) and transdermal bioavailability (76%) within expected ranges. The estimated fraction of the dose swallowed for buccal formulations ranged from 55% (gum) to 69% (lozenge). CONCLUSIONS: Robust population pharmacokinetic models were developed for five nicotine replacement therapy product types and for intravenous and oral nicotine. These population pharmacokinetic models are used in exposure-response analyses and simulation-based nicotine replacement therapy product design.

Relating Nicotine Plasma Concentration to Momentary Craving Across Four Nicotine Replacement Therapy Formulations.

Tobacco use is a major health concern. To assist smoking cessation, nicotine replacement therapy (NRT) is used to reduce nicotine craving. We quantitatively described the relationship between nicotine pharmacokinetics (PKs) from NRTs and momentary craving, linking two different pharmacodynamic (PD) scales for measuring craving. The dataset comprised retrospective data from 17 clinical studies and included 1,077 adult smokers with 39,802 craving observations from four formulations: lozenge, gum, mouth spray, and patch. A PK/PD model was developed that linked individual predicted nicotine concentrations with the categorical and visual analogue PD scales through a joint bounded integer model. A maximum effect model, accounting for acute tolerance development, successfully related nicotine concentrations to momentary craving. Results showed that all formulations were similarly effective in reducing craving, albeit with a fourfold lower potency for the patch. Women were found to have a higher maximal effect of nicotine to reduce craving, compared with men.