Population Pharmacokinetic-Pharmacodynamic Model of Craving in an Enforced Smoking Cessation Population: Indirect Response and Probabilistic Modeling

Abstract

Purpose. A population pharmacokinetic-pharmacodynamic model accounting for placebo effect was used to relate nicotine concentration and enforced smoking cessation craving score measured by the Tiffany rating scale short form.

Methods. Twenty-four smokers were enrolled in a placebo-controlled, randomized, double-blind, three periods, crossover trial. The study objective was to describe the nicotine-induced changes on craving scores. Two modeling strategies based on a mechanistic (indirect response models with drug-related inhibition on the k_in synthesis rate and with a drug-related stimulation of the k_out removal rate were evaluated) and a probabilistic (logistic regression) approach were used.

Results. Placebo response model properly fitted the circadian changes on craving scores. The analysis revealed that the indirect response model with inhibition on k_in was the preferred model for the smoking data whereas the preferred model for the Nicotine Replacement Therapy data was the one with stimulation on k_out. The logistic analysis showed that the nicotine concentration was a significant predictor of reduction in craving during the free-smoking period.

Conclusions. Nicotine dosage regimen can influence the nicotine mechanism of action: an instantaneous delivery at an individually selected time seems to inhibit the onset of craving while constant delivery at a pre-defined time seems to attenuate the craving.