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

Abstract

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.

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

“…This might indicate that for individual smokers with a motivation to stop smoking, successfully managing their craving is of major importance for the success of their attempt to quit smoking. NRT reduces craving through nicotine concentrations, which has previously been shown 15 and thus NRT reduced the risk of relapse mediated by craving. Although no covariate analysis was performed in this current work, craving has been shown to be higher for men and subjects with a short "time until first cigarette", thus implicitly these covariates also affects the risk of relapse.…”

“…As integrated craving was measured with three different scales, a bounded integer, 25,26 mixed-effects model was developed for integrated craving, similar to our previous work with momentary craving. 15 This model translated the observed score (dependent on scale) to a latent variable, called 'Latent Integrated Craving', which is independent of scale. The model described the changes of latent integrated craving (LIC) over time.…”

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

“…The PPK models developed in this research were used to conduct nicotine exposure-response analyses linking nicotine exposure to momentary craving and smoking cessation, as published elsewhere [28,43]. The PPK and the exposure-response models were used to build a simulation platform that is being used to (i) maximise the value of the existing products by understanding the effect of different dosing scenarios, including combinations treatments, in momentary craving and (ii) streamline the development of new NRT products by leveraging the nicotine PKPD knowledge in identifying the appropriate nicotine dose and delivery rate of a new product to achieve a desired momentary craving effect, and optimising the PKPD information that needs to be collected from the clinical studies of new products or combinations.…”

“…A time-dependent increase in CL or decrease in F was required to model the lower than expected plasma concentrations at steady state for repeated-dose oral and buccal administrations. These models can be, and have been, used for Bayesian prediction of concentration-time profiles for use in exposure-response analysis [28], and for simulation of various dosing scenarios.…”

“…We integrated data across a broad range of nicotine formulations and studies by developing predictive PPK models. This further increased our understanding of nicotine pharmacokinetics and its link with craving through exposure-response analyses, aiming to better understand and optimise the use of NRT [28]. Together, these models allow simulations of various dosing scenarios, e.g.…”